SYNTHESIS: To a clear solution of 40.4 g flake KOH in 400 mL warm EtOH
there was added 86.5 g 2,3-xylenol followed by 51.4 g methyl iodide.
This mixture was held at reflux for 2 days, stripped of volatiles
under vacuum, the residues dissolved in 1 L of H2O, and extracted with
4x200 mL CH2Cl2. The pooled extracts were washed with 5% NaOH until
the washes remained basic. Following a single washing with dilute
HCl, the solvent was removed under vacuum, and the residue, 41.5 g of
a pungent smelling amber oil, spontaneously crystallized. The mp of
2,3-dimethylanisole was 25-26 °C and it was used without further
purification in the next step. From the aqueous basic washes,
following acidification, extraction, and solvent removal, there was
obtained 46.5 g crude unreacted xylenol which could be recycled.
A mixture of 205 g POCl3 and 228 g N-methylformanilide was allowed to
incubate at room temperature until there was the development of a deep
claret color with some spontaneous heating. To this, there was added
70.8 g 2,3-dimethylanisole, and the dark reaction mixture heated on
the steam bath for 2.5 h. The product was then poured into 1.7 L H2O,
and stirred until there was a spontaneous crystallization. These
solids were removed by filtration, H2O washed and air dried to give
77.7 g of crude benzaldehyde as brown crystals. This was distilled at
70-90 °C at 0.4 mm/Hg to give 64.8 g of
2,3-dimethyl-4-methoxybenzaldehyde as a white crystalline product with
a mp of 51-52 °C. Recrystallization from MeOH produced an analytical
sample with a mp of 55-55.5 °C. Anal. (C10H12O2) C,H. The
malononitrile derivative (from the aldehyde and malononitrile in EtOH
with a drop of triethylamine) had a mp of 133-133.5 °C from EtOH.
Anal. (C13H12N2O) C,H,N. Recently, this aldehyde has become
commercially available.
A solution of 32.4 g 2,3-dimethyl-4-methoxybenzaldehyde in 800 mL
CH2Cl2 was treated with 58.6 g 85% m-chloroperoxybenzoic acid and held
at reflux for 3 days. After cooling to room temperature, the white
solids (m-chlorobenzoic acid) were removed by filtration (about 40 g
when dry). The filtrate was extracted with several portions of
saturated NaHCO3 (on acidification, this aqueous wash yielded
additional m-chlorobenzoic acid) and the organic solvent removed under
vacuum. The crystalline residue (weighing 32 g and deeply colored)
was dissolved in 150 mL boiling MeOH to which there was added 18 g of
solid NaOH and the solution heated on the steam bath for a few min.
The mixture was added to 800 mL H2O, and a little surface scum
mechanically removed with a piece of filter paper. The solution was
acidified with concentrated HCl, depositing 30.9 g of a tan solid.
Recrystallization from H2O gave 2,3-dimethyl-4-methoxyphenol as white
needles, with a mp of 95-96 °C. Anal. (C9H12O2) H; C: calcd, 71.06;
found 70.20. The N-methyl carbamate was made by the treatment of a
solution of the phenol (1 g in 75 mL hexane with 5 mL CH2Cl2 added)
with 2 g methyl isocyanate and a few drops of triethyl amine. The
pale pink solids that separated were recrystallized from MeOH to give
a product that had a mp of 141-142 °C. Anal. (C11H15NO3) C,H,N.
To a solution of 23.1 g flake KOH in 250 mL hot EtOH there was added
61.8 g 2,3-dimethyl-4-methoxyphenol followed by 60 g methyl iodide.
This was held under reflux for 12 h, then stripped of solvent under
vacuum. The residue was dissolved in 1.2 L H2O, acidified with HCl,
and extracted with 3x200 mL CH2Cl2. The combined extracts were washed
with 3x100 mL 5% NaOH, and the solvent was removed under vacuum. The
residue set up as an off-white mass of leaflets weighing 37.7 g after
filtering and air drying. Recrystallization from MeOH gave
2,3-dimethyl-1,4-dimethoxybenzene as white solids, with a mp of 78-79
°C. Anal. (C10H14O2) C,H. An alternate route leading from
2,3-xylenol to this diether via nitrogen-containing intermediates was
explored. The sequence involved the reaction of 2,3-xylenol with
nitrous acid (4-nitroso product, mp 184 °C dec.), reduction with
sodium dithionite (4-amino product, mp about 175 °C), oxidation with
nitric acid (benzoquinone, mp 58 °C), reduction with sodium dithionite
(hydro-quinone) and final methylation with methyl iodide. The yields
were inferior with this process.
A mixture of 88 g POCl3 and 99 g N-methylformanilide was allowed to
incubate until a deep claret color had formed, then it was treated
with 36.5 g 2,3-dimethyl-1,4-dimethoxybenzene and heated on the steam
bath for 3 h. It was then poured into 1 L H2O, and stirred until the
formation of a loose, crumbly, dark crystalline mass was complete.
This was removed by filtration, and dissolved in 300 mL CH2Cl2. After
washing first with H2O, then with 5% NaOH, and finally with dilute
HCl, the solvent was removed under vacuum yielding 39.5 g of a black
oil that solidified. This was extracted with 2x300 mL boiling hexane,
the extracts were pooled, and the solvent removed under vacuum. The
yellowish residue crystallized to give 32.7 g
2,5-dimethoxy-3,4-dimethylbenzaldehyde with a mp of 46-47 °C.
Repeated recrystallization from MeOH raised the mp to 59-60 °C. The
malononitrile derivative was prepared (aldehyde and malononitrile in
EtOH with a few drops triethyl amine) as yellow crystals from EtOH,
with a mp of 190-191 °C. Anal. (C14H14N2O2) C,H; N: calcd, 11.56;
found, 11.06, 11.04.
To a solution of 16.3 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde in 50
mL nitromethane there was added 3.0 g anhydrous ammonium acetate, and
the mixture was heated on the steam bath overnight. There was then
added an equal volume of MeOH, and with cooling there was obtained a
fine crop of yellow crystals. These were removed by filtration,
washed with MeOH, and air dried to provide 4.4 g of
2,5-dimethoxy-3,4-dimethyl-beta-nitrostyrene with a mp of 120-121 °C
which was not improved by recrystallization from MeOH (50 mL/g). The
mother liquors of the above filtration were diluted with H2O to the
point of permanent turbidity, then set aside in a cold box. There was
a chunky, granular, tomato-red crystal deposited which weighed 2.5 g
when dry. It had a mp of 118-119.5 °C, which was undepressed in mixed
mp with the yellow sample. Both forms had identical NMR spectra
(2.20, 2.25 CH3; 3.72, 3.84 OCH3; 6.80 ArH; 7.76, 8.28 CH=CH, with 14
cycle splitting), infrared spectra, ultra violet spectra (max. 324 nm
with shoulder at 366 nm in EtOH, two peaks at 309 and 355 nm in
hexane), and microanalyses. Anal. (C12H15NO4) C,H,N.
A solution of LAH (56 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 1.52 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 3.63 g
2,5-dimethoxy-3,4-dimethyl-beta-nitrostyrene in 36 mL anhydrous THF over
the course of 1 h. After a few minutes further stirring, the
temperature was brought up to a gentle reflux on the steam bath for
about 5 min, then all was cooled again to 0 °C. The excess hydride
was destroyed by the cautious addition of 9 mL IPA followed by 2.5 mL
15% NaOH and finally 7.5 mL H2O. The reaction mixture was filtered,
and the filter cake washed first with THF and then with IPA. The
filtrate was stripped of solvent under vacuum and the residue was
distilled at 110-120 °C at 0.2 mm/Hg to give 2.07 g of
2,5-dimethoxy-3,4-dimethylphenethylamine as a clear white oil. This
was dissolved in 10 mL IPA, neutralized with concentrated HCl, and
then diluted with 25 mL anhydrous Et2O. The crystals that formed were
filtered, Et2O washed, and air dried to constant weight. There was
obtained 2.13 g of beautiful white crystals of
2,5-dimethoxy-3,4-dimethylphenethylamine hydrochloride (2C-G) with a
mp of 232-233 °C. Anal. (C12H20ClNO2) C,H.
DOSAGE: 20 - 35 mg.
DURATION: 18 - 30 h.
QUALITATIVE COMMENTS: (with 22 mg) I am completely functional, with
writing and answering the telephone, but the coffee really tastes most
strange. While the mental effects (to a ++ only) were dispersing, the
body still had quite a bit of memory of the day. Sleep was fine, and
desirable, in the early evening.
(with 32 mg) Superb material, to be classified as a 'true
psychedelic' unless one is publishing, in which case it could be best
described as an 'insight-enhancer' and obviously of potential value in
psychotherapy (if one would wish to spend 30 hours in a therapy
session!). I suppose it would be best to simply stick with the
insight-enhancing and skip the psychotherapy. Just too, too long.
There was not any particular visual impact, at least for me. The
non-sexual and the anorexic aspects might indeed change, with
increasing familiarity. Remains to be seen. The length of the
experience is against its frequent use, of course, which is a pity,
since this one is well worth investigating as often as possible.
(with 32 mg) There was, at the very beginning, a certain feeling of
non-physical heat in the upper back which reminded me of the onset of
various indoles, which this ain't. The energy tremor was quite strong
throughout, but somehow the body was generally at ease.
(with 32 mg) At a plateau at two hours, with just a bit of tummy
queasi-ness. And I am still at the plateau several hours later.
Sleep finally at the 18th hour, but even after getting up and doing
all kinds of things the next day, I was not completely baseline until
that evening. And a couple of days more for what is certainly
complete repair. That is a lot of mileage for a small amount of
material.
EXTENSIONS AND COMMENTARY: Here is the first example, ever, of a
phen-ethylamine that is of about the same potency as therelated
three-carbon amphetamine. At first approximation, one is hard put to
distinguish, from the recorded notes, any major differences either in
potency, in duration, or in the nature of activity, between 2C-G and
GANESHA itself.
I had always thought of the phenethylamines as being somewhat weaker
than the corresponding amphetamines. Sometimes a little weaker and
sometimes a lot weaker. But that is a totally prejudiced point of
view, an outgrowth of my earliest comparisons of mescaline and TMA.
That's the kind of thing that can color one's thinking and obscure
what may be valuable observations. It is equally valid to think of
the phenethylamines as the prototypes, and that the amphetamines are
somewhat stronger than the corresponding phenethylamines. Sometimes a
little stronger and sometimes a lot stronger. Then the question
suddenly shifts from asking what is different about the
phenethylamines, to what is different about the amphetamines? It is
simply a historic fact, that in most of my exploring, the amphetamine
was made and evaluated first, and so tended to slip into the role of
the prototype. In any case, here the two potencies converge.
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