This is a recipe from
PiHKAL. If you're interested in how the hardlinks
were chosen, read
noding PiHKAL for Everything2.
#76 EMM
4,5-DIMETHOXY-2-ETHOXYAMPHETAMINE
SYNTHESIS: A
solution of 166 g
3,4-dimethoxybenzaldehyde in 600 mL
acetic acid was well stirred, and brought up to an internal
tem
perature of exactly 25 °C. There was added, in very small
portions, a 40%
solution of
peracetic acid in acetic acid. The
evolved heat was removed with an external ice bath, and the rate of
addition was dictated by the requirement that the internal tem
perature
should not exceed 25 °C. A total of 210 g of the 40%
peracetic acid
was used. The reaction mixture was poured into 3 L H2O, and the
acetic acid neutralized by the addition of solid
K2CO3. The neutral
aqueousphase was extracted with 5x150 mL
Et2O, and the
solvent from
the pooled extracts was removed under vacuum. To the red-colored
residue there was added 300 mL 10%
NaOH, and the mixture was heated
for 1 h on the steam bath. This was cooled, washed once with
CH2Cl2,
acidified with HCl, and extracted with 5x150 mL
Et2O. The pooled
extracts were washed once with saturated
NaHCO3 (which removed most of
the color) and the removal of the
solvent under vacuum gave 105 g of
3,4-dimethoxyphenol as an amber oil that slowly set up to
crystals.
The above crude
3,4-dimethoxyphenol was
dissolved in 200 mL
EtOH, and
treated with a
solution of 38.1 g KOH in 300 mL hot
EtOH. The clear
solution of the
potassium salt was a deep red color, and was promptly
treated with 94.3 g allyl
bromide, at a rate commensurate with the
exothermic reaction. The mixture was held at reflux for 2 h. This
was then added to 1 L H2O and extracted with 5x100 mL
Et2O. The
extracts were pooled, and removal of the
solvent under vacuum gave a
residue of 98 g of a black oil. This was
distilled at 104-108 °C at
0.7-1.0 mm/
Hg to give 59.3 g
1-allyloxy-3,4-dimethoxybenzene as a pale
yellow oil with a greenish cast.
A total of 59 g of the neat
1-allyloxy-3,4-dimethoxybenzene was
provided with an internal thermometer, and heated with an open flame.
The color quickly became purple, then lightened to a red at 70 °C, and
finally to a pale pink by 210 °C. At 240 °C an exothermic reaction
set in with the tem
perature going up to almost 290 °C. It was held in
the 270-280 °C range for several min, then allowed to return to room
tem
perature. GC analysis showed two peaks, the second and major one
being the desired
1,2,4,5-isomer. A small sample was caught by
prep-GC, and it successfully seeded the crude
Claissen rearrangement
product. The isolated
2-allyl-4,5-dimethoxyphenol, pressed on a
porous plate, had a mp of 39.5-40.5 °C which was improved to 41.5-42
°C by re
crystallization from hexane.
To a
solution of 9.7 g
2-allyl-4,5-dimethoxyphenol in a few mL
EtOH,
there was added a
solution of 2.8 g KOH in 25 mL boiling
EtOH followed
by 5.5 g
ethyl bromide. The mixture was held at reflux for 3.5 h and
then poured into 200 mL H2O and extracted with 3x100 mL
CH2Cl2.
Pooling the extracts and removal of the
solvent under vacuum gave a
residue of 10.4 g of
4,5-dimethoxy-2-ethoxy-1-allylbenzene as a clear,
mobile oil. It was substantially a single component by GC and was
used in the following
isomerization step without further purification.
A
solution of 9.4 g
4,5-dimethoxy-2-ethoxy-1-allylbenzene in 10 mL
EtOH was treated with 20 g flaked KOH, and heated on the steam bath.
The progress of the
isomerization was followed by the assay of
isolates by GC. After 5 h, the reaction mixture was poured into 250
mL H2O which immediately generated a pasty solid. This was sucked
free of
solvent and other liquids on a sintered funnel, giving 5.5 g
of
trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene as an amber solid
with a mp of 65-67 °C. A small
analytical sample from hexane had a mp
of 68 °C.
A
solution of 5.0 g
trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene in
27 g
acetone that contained 2.2 g
pyridine was
magnetically stirred
and cooled to 0 °C. There was then added 4.5 g
tetranitromethane and,
after 2 minutes stirring at this tem
perature, the reaction mixture was
quenched with a
solution of 1.5 g KOH in 26 mL H2O. The reaction
mixture remained a clear deep orange color, and additional H2O was
required to institute
crystallization. There was the slow
deposition
of bright yellow
crystals of
1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitro-propene which weighed, after
EtOH washing and air drying to constant weight of 4.4 g. The mp was
75-76 °C.
To a gently refluxing suspension of 3.5 g LAH in 250 mL
anhydrous Et2O
under a He
atmosphere, there was added 3.9 g
1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitropropene by allowing the
condensing
Et2O to drip into a shunted Soxhlet apparatus with the
thimble containing the
nitrostyrene. This effectively added a warm
saturated
solution of the
nitrostyrene dropwise; the nitrostyrene was
very
soluble in
Et2O.
Refluxing was maintained for 2.5 h and the
reaction continued to stir at room tem
perature for an additional 3.5
h. The excess
hydride was destroyed by the cautious addition of 225
mL 1.5 N H2SO4. When the aqeous and
Et2O layers were finally clear,
they were separated, and 75 g of
potassium sodium tartrate was
dissolved in the aqueous fraction. Aqueous
NaOH was then added until
the
pH was >9, and this was then extracted with 3x100 mL
CH2Cl2.
Evaporation of the
solvent under vacuum produced 2.8 g of a clear,
almost colorless oil that was
dissolved in
anhydrous Et2O and
saturated with
anhydrous HCl gas. This initially generated a solid
that then oiled out. After a few minutes stirring, this began to
solidify again and it finally transformed into a loose fine white
solid. This was re
crystallized by
dissolution in 50 mL warm IPA
followed by
dilution with 300 mL
Et2O. After a few minutes,
crystals
of
4,5-dimethoxy-2-ethoxyamphetamine hydrochloride (EMM) formed which
were removed by filtration,
Et2O washed, and air dried. These weighed
2.7 g and had a mp of 171-172 °C. Anal. (
C13H22ClNO3) C,H,N.
DOSAGE: greater than 50 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 50 mg) There were no effects.
EXTENSIONS AND COMMENTARY: This was the first of the ethoxy
homologues
of TMA-2, and it was immediately (well, within a couple of months) run
up from an initial dab to 25 milligrams. This was in early 1963, and
the lack of activity of EMM was keenly disappointing. This was a
level at which the prototype, TMA-2, was very active, and the
conclusion was that maybe any change on the molecule would result in a
loss of activity. So this approach was shelved for a while, and all
efforts were directed into the relocation, rather than the elongation,
of the methoxy groups. A few months later, the ethoxy question was
addressed again, and the discovery of
MEM rekindled full interest in
this ethoxy question.
Back to PiHKAL?