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#28 2C-G-3
2,5-DIMETHOXY-3,4-(TRIMETHYLENE)PHENETHYLAMINE; 5-(2-AMINOETHYL)-4,7-DIMETHOXYINDANE)
SYNTHESIS: To a
solution of 22 g of KOH in 250 mL of hot
EtOH, there
was added 50 g of 4-indanol and 75 g
methyl iodide. The mixture was
held at reflux for 12 h. There was then added an additional 22 g KOH
followed by an additional 50 g of
methyl iodide.
Refluxing was
continued for an additional 12 h. The mixture was poured into 1 L
H2O, acidified with HCl, and extracted with 3x75 mL
CH2Cl2. The pooled
extracts were washed with 5%
NaOH, then with dilute HCl, and the
solvent was removed under vacuum. The residue of crude
2,3-(trimethylene)anisole weighed 56.5 g and was used without further
purification in the following reaction.
A mixture of 327 g N-
methylformanilide and 295 g POCl3 was allowed to
incubate until a deep claret color had formed. To this there was then
added 110 g of crude
2,3-(trimethylene)anisole, and the mixture heated
on the steam bath. There was a vigorous evolution of gases, which
largely quieted down after some 4 h of heating. The reaction mixture
was added to 4 L H2O and stirred overnight. The oily aqueous
phase
was extracted with 3x200 mL
CH2Cl2, and after combining the extracts
and removal of the
solvent there was obtained 147 g of a black,
sweet-smelling oil. This was
distilled at 182-194 °C at the water
pump to yield 109.1 g of a pale yellow oil. At low tem
perature, this
crystallized, but the solids melted again at room tem
perature. Gas
chromatography of this product on OV-17 at 185 °C showed detectable
starting
anisole and N-
methylformanilide (combined, perhaps 5% of the
product) and a small but real
isomeric peak, (about 5%, slightly
faster moving than the title
aldehyde, again about 5% of the product)
of what was tentatively identified as the ortho-
aldehyde
(
2-methoxy-3,4-(trimethylene)-benzaldehyde). The bulk of this crude
product (74 g) was re
distilled at 110-130 °C at 0.3 mm/
Hg to give 66 g
of
4-methoxy-2,3-(trimethylene)benzaldehyde as a nearly colorless oil
which set up as a
crystalline solid. A portion on porous plate showed
a mp of 28-29 C. A gram of this
aldehyde and a gram of
malononitrile
in 25 mL of
EtOH was treated with a few drops of
triethylamine and
gave pale yellow
crystals of the
malononitrile derivative. This, upon
re
crystallization from 50 mL boiling
EtOH, had a mp of 176-176.5 °C.
Anal. (
C14H12N2O) C,H,N. A side path, other than towards the intended
targets 2C-G-3 and G-3, was explored. Reaction with
nitroethane and
anhydrous ammonium acetate gave the
2-nitropropene analogue which was
obtained in a pure state (mp 74-75 °C from MeOH) only after repeated
extraction of the crude isolate with boiling hexane. Reduction with
elemental iron gave the
phenylacetone analogue which was reductively
aminated with
dimethylamine and
sodium cyanoborohydride to give
N,N-
dimethyl-
4-methoxy-2,3-(trimethylene)amphetamine. This was
designed for brain blood-flow volume studies after
iodination at the
5-position, a concept that has been discussed under IDNNA. It has
never been tasted by anyone. The corresponding primary
amine,
4-methoxy-2,3-(trimethylene)amphetamine has not yet even been
synthesized.
A
solution of 34.8 g
4-methoxy-2,3-(trimethylene)benzaldehyde in 800
mL
CH2Cl2 was treated with 58.6 g of 85% m-
chloroperoxybenzoic acid
and held at reflux for 3 days. After cooling and standing for a few
days, the solids were removed by filtration and washed sparingly with
CH2Cl2. The combined filtrate and washings were washed with 200 mL
saturated
NaHCO3, and the
solvent removed, yielding 43.5 g of a deeply
colored oil. This was
dissolved in 150 mL MeOH to which was added 9 g
NaOH and all heated to reflux on the steam bath. After 1 h, a
solution of 9 g
NaOH in 20 mL H2O was added, heated further, then
followed by yet another treatment with 9 g
NaOH in 20 mL H2O followed
by additional heating. All was added to 800 mL H2O, washed once with
CH2Cl2 (which removed a trivial amount of material) and then acidified
with HCl. The dark
crystals that were generated were filtered and air
dried to constant weight, yielding 27.5 g dark but nice-looking
crystals with a mp of 89-91 °C. By all counts, this should have been
the product
phenol,
4-methoxy-2,3-(trimethylene)phenol, but the
microanalysis indicated that the
formate ester was still there. Anal.
(
C10H12O2) requires C = 73.08, H = 7.37. (
C11H12O3) requires C =
68.73, H = 6.29. Found: C = 69.04, 68.84; H = 6.64, 6.58. Whatever
the exact chemical status of the
phenolic hydroxyl group might have
been, it reacted successfully in the following
methylation step.
To a
solution of 10 g KOH in 100 g
EtOH (containing 5% IPA) there was
added 27.5 g of the above 89-91 °C melting material, followed by 25 g
methyl iodide. The mixture was held at reflux overnight. All was
added to 800 mL H2O, acidified with HCl, and extracted with 3x100 mL
CH2Cl2. The combined extracts were washed with 3x100 mL 5%
NaOH, then
once with dilute HCl, and the
solvent removed under vacuum yielding
20.4 g of a fragrant
crystalline residue. This was re
crystallized
from 60 mL boiling MeOH to give, after filtering and air drying, 16.0
g of
1,4-dimethoxy-2,3-(trimethylene)benzene (
4,7-dimethoxyindane)
with a mp of 86-88 °C. Anal. (
C11H14O2) C,H.
To a mixture of 39.0 g of N-
methylformanilide and 35.9 g POCl3 that
had been allowed to stand at ambient tem
perature until deeply claret
(about 45 min) there was added 15.8 g of
1,4-dimethoxy-2,3-(trimethylene)benzene. The mixture was heated on
the steam bath for 4 h and then poured into 600 mL H2O. After
stirring overnight there was produced a heavy
crystalline mass. This
was removed by filtration and, after air drying, was extracted with
3x100 mL boiling hexane. Pooling and cooling these extracts yielded
9.7 g of salmon-colored
crystals with a mp of 67-68 °C. This was
re
crystallized from 25 mL boiling
EtOH to give, after filtration, EtOH
washing, and air drying to constant weight, 7.4 g of
2,5-dimethoxy-3,4-(trimethylene)benzaldehyde, with a mp of 71-72 °C.
The mother liquors on cautious treatment with H2O, yielded, after
EtOH
re
crystallization, 1 g additional product. Anal. (
C12H14O3) C,H. A
solution of 150 mg
aldehyde and an equal weight of
malononitrile in
2.3 mL
EtOH treated with 3 drops
triethylamine gave immediate yellow
crystals of the
malononitrile derivative, with a mp of 161-162 °C.
Anal. (
C15H14N2O2) C,H,N.
A
solution 3.7 g
2,5-dimethoxy-3,4-(trimethylene)benzaldehyde in 15 g
nitromethane was treated with 0.7 g
anhydrous ammonium acetate and
heated on the steam bath for 14 h. The
volatiles were removed under
vacuum, and the residue set up to 3.5 g dark
crystals, which melted
broadly between 126-138 °C. Re
crystallization of the entire mass from
70 mL boiling
EtOH gave 3.2 g burnished gold
crystals with a mp of
129-137 °C. A further re
crystallization of an
analytical sample from
MeOH gave
2,5-dimethoxy-3,4-(trimethylene)-beta-nitrostyrene as yellow
crystals with a mp of 146-147 °C. Anal. (
C13H15NO4) C,H.
To a cold
solution of LAH in THF (40 mL of a 1 M solution) well
stirred and under an inert
atmosphere, there was added dropwise 1.05
mL freshly prepared 100% H2SO4. There was then added, dropwise, a
solution of 2.39 g
2,5-dimethoxy-3,4-(trimethylene)-beta-nitrostyrene in
25 mL THF. The bright yellow color was discharged immediately. After
the addition was complete, stirring was continued for an additional 20
min, and the reaction mixture brought to a reflux on the steam bath
for another 0.5 h. After cooling, the excess
hydride was destroyed
with IPA (8 mL required) followed by sufficient 15%
NaOH to convert
the inorganics into a loose, filterable mass. This was removed by
filtration, and the filter cake washed with THF. The combined
filtrate and washes were stripped of
solvent under vacuum, and the
residue
dissolved in dilute H2SO4. After washing with
CH2Cl2, the
aqueous
phase was made basic with 25%
NaOH and extracted with 3x75 mL
CH2Cl2. After removal of the
solvent under vacuum, the residue was
distilled at 125-160 °C at 0.45 mm/
Hg to yield 0.80 g of a white oil.
This was
dissolved in 8 mL IPA, neutralized with 20 drops of
concentrated HCl (the salt
crystals started to form before this was
completed) followed with the addition of 65 mL
anhydrous Et2O. The
white
crystalline mass was filtered, washed with
Et2O, and air dried
to provide 1.16 g of
2,5-dimethoxy-3,4-(trimethylene)phenethylamine
hydrochloride (2C-G-3) with a mp of 214-216 °C with decomposition.
Anal. (
C13H20ClNO2) C,H.
DOSAGE: 16 - 25 mg.
DURATION: 12 - 24 h.
QUALITATIVE COMMENTS: (with 16 mg) It came on in little leaps and
bounds. All settled, and then it would take another little jump
upwards. I am totally centered, and writing is easy. My appetite is
modest. Would I drive to town to return a book to the library? No
ever-loving way! I am very content to be right here where I am safe,
and stay with the writing. It does take so much time to say what
wants to be said, but there is no quick way. A word at a time.
(with 22 mg) I walked out for the mail at just about twilight. That
was the most courageous thing that I could possibly have done, just
for one lousy postcard and a journal. What if I had met someone who
had wanted to talk? Towards evening I got a call from Peg who said
her bean soup was bubbling in a scary way and what should she do, and
I said maybe better make soap. It was that kind of an experience!
Way up there, lots of LSD-like sparkles, and nothing quite really
making sense. Marvelous.
(with 25 mg) There was easy talking, and no hint of any body concern.
Sleep that evening was easy, and the next day was with good energy.
EXTENSIONS AND COMMENTARY: The positives of a completely intriguing
altered state free from apparent physical threats, are here coupled
with the negative of having to invest such a long period of time.
There is a merry nuttiness which can give a joyous intoxication, but
with the underlying paranoia of how it looks to others. There is an
ease of communication, but only within surroundings that are
well-known and friendly. This might be a truly frightening experience
if it were in an unfamiliar or unstructured environment.
The numbering of this compound, and all the extensions of GANESHA,
have been made on the basis of the nature of the stuff at the
3,4-position. Here there are three atoms (the
trimethylene bridge)
and so 2C-G-3 seems reasonable. With this logic, the
dimethylene
bridge would be 2C-G-2 (and the corresponding
amphetamine would be
G-2, of course). But these compounds call upon a common intermediate
which is a
benzocyclobutene, OK in principle but not yet OK in
practice. The right
benzyne reaction will be there someday, and the
dimethylene analogues will be made and assayed. But, in the meantime,
at least the names have been assigned.
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