SYNTHESIS: To 27 g 1,3-dimethoxybenzene that was being well stirred,
there was added, dropwise, 29 g concentrated H2SO4 over a period of 15
min. Stirring was continued for 1 hour, and then the mixture was
poured slowly into 250 mL of saturated aqueous K2CO3. The precipitate
that formed was removed by filtration, and dried at 125 °C to give
59.6 g crude potassium 2,4-dimethoxybenzenesulfonate. This was finely
ground, and 30 g of it was treated with 35 g of POCl3 and the mixture
heated on the steam bath for 2 h. This was cooled to room
temperature, and then poured over 300 mL crushed ice. When all had
thawed, this was extracted with 2x150 mL Et2O. The extracts were
pooled, washed with saturated brine, and the solvent removed under
vacuum to give a residue which solidified. There was thus obtained
14.2 g 2,4-dimethoxybenzenesulfonyl chloride as white solids with a mp
of 69-72 °C. Heating of a small portion with concentrated ammonium
hydroxide gave the corresponding sulfonamide which, on
recrystallization from EtOH, produced white needles with a mp of
165.5-166.5 °C.
To a stirred and gently refluxing suspension of 11 g LAH in 750 mL
anhydrous Et2O, there was added 13.2 g 2,4-dimethoxybenzenesulfonyl
chloride in an Et2O solution. The refluxing was maintained for 48 h
then, after cooling externally with ice water, the excess hydride was
destroyed by the slow addition of 600 mL of 10% H2SO4. The phases
were separated, and the aqueous phase extracted with 2x200 Et2O. The
organics were pooled, washed once with 200 mL H2O, and the solvent
removed under vacuum. The residue was dried azeotropically through
the addition and subsequent removal of CH2Cl2. Distillation of the
residue provided 8.0 g 2,4-dimethoxythiophenol as a colorless oil,
boiling at 89-92 °C at 0.5 mm/Hg.
To a solution of 7.8 g 2,4-dimethoxythiophenol in 40 mL absolute EtOH
there was added a solution of 4 g 85% KOH in 65 mL EtOH. This was
followed by the addition of 5 mL methyl iodide, and the mixture was
held at reflux for 30 min. This was poured into 200 mL H2O, and
extracted with 3x50 mL Et2O. The pooled extracts were washed once
with aqueous sodium hydrosulfite, then the organic solvent was removed
under vacuum. The residue was distilled to give 8.0 g of
2,4-dimethoxythioanisole as a colorless oil with a bp of 100-103 °C at
0.6 mm/Hg.
To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been
warmed briefly on the steam bath there was added 7.8 g of
2,4-dimethoxythioanisole. The reaction was heated on the steam bath
for an additional 20 min and then poured into 200 mL H2O. Stirring
was continued until the insolubles had become completely loose and
granular. These were removed by filtration, washed with H2O, sucked
as dry as possible, and then recrystallized from boiling MeOH. The
product, 2,4-dimethoxy-5-(methylthio)benzaldehyde, was an off-white
solid weighing 8.6 g. It could be obtained in either of two
polymorphic forms, depending on the concentration of aldehyde in MeOH
at the time of crystal appearance. One melted at 109-110 °C and had a
fingerprint IR spectrum including peaks at 691, 734, 819 and 994 cm-1.
The other melted at 124.5-125.5 °C and had major fingerprint peaks at
694, 731, 839 and 897 cm-1. Anal. (C10H12O3S) C,H.
A solution of 8.2 g 2,4-dimethoxy-5-(methylthio)benzaldehyde in 30 mL
nitroethane was treated with 1.8 g anhydrous ammonium acetate and
heated on the steam bath for 4 h. Removal of the excess nitroethane
under vacuum gave a colored residue which crystallized when diluted
with MeOH. Recrystallization of the crude product from boiling EtOH
gave, after filtration, washing and air drying to constant weight, 8.3
g 1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene with a mp of
112-113 °C. Anal. (C12H15NO4S) C,H,N.
A suspension of 6.5 g LAH in 250 mL anhydrous THF was placed under a
N2 atmosphere and stirred magnetically and brought to reflux. There
was added, dropwise, 8.0 g of
1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene in 50 mL THF. The
reaction mixture was maintained at reflux for 18 h. After being
brought to room temperature, the excess hydride was destroyed by the
addition of 6.5 mL H2O in 30 mL THF. There was then added 6.5 mL of
3N NaOH, followed by an additional 20 mL H2O. The loose, white,
inorganic salts were removed by filtration, and the filter cake washed
with an additional 50 mL THF. The combined filtrate and washes were
stripped of solvent under vacuum yielding a residue that was
distilled. The free base boiled at 125-128 °C at 0.1 mm/Hg and was a
white oil which solidified on standing. It weighed 5.1 g and had a mp
of 47-48.5 °C. This was dissolved in 50 mL IPA, neutralized with
concentrated HCl (until dampened universal pH paper showed a deep red
color) and diluted with anhydrous Et2O to the point of turbidity.
There was a spontaneous crystallization providing, after filtering,
washing with Et2O, and air drying,
2,4-dimethoxy-5-methylthioamphetamine hydrochloride (META-DOT) with a
mp of 140.5-142 °C. Anal. (C12H20ClNO2S) C,H,N.
DOSAGE: greater than 35 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 35 mg) There was a vague awareness of
something all afternoon, something that might be called a thinness.
Possibly some brief cardiovascular stimulation, but nothing completely
believable. This is a threshold level at the very most.
EXTENSIONS AND COMMENTARY: Again, as with the studies with ORTHO-DOT,
it is apparent that the activity of META-DOT is going to be way down
from the most interesting of these isomers, PARA-DOT (ALEPH-1, or just
ALEPH). In the rectal hyperthermia assay (which calculates the
psychedelic potential of compounds by seeing how they influence the
body temperature of experimental animals in comparison to known
psychedelics) the three DOT's were compared with DOM. And the results
fell into line in keeping with the activities (or loss of activities)
found in man. PARA-DOT was about half as active as DOM, but both
ORTHO-DOT and the compound described here, META-DOT, were down by
factors of 50x and 30x respectively. These animal studies certainly
seem to give results that are reasonable with a view to other known
psychedelic drugs, in that mescaline was down from DOM by a factor of
more than 1000x, and LSD was some 33x more potent than DOM.
I have a somewhat jaundiced view of this rabbit rectal hyperthermia
business. One is presumably able to tell whether a compound is a
stimulant or a psychedelic drug by the profile of the temperature
rise, and how potent it will be by the extent of the temperature rise.
But the concept of pushing thermocouples into the rear ends of
restrained rabbits somehow does not appeal to me. I would rather
determine both of these parameters from human studies.
Back]
]