SYNTHESIS: A solution of 9.0 g 2,5-dibromotoluene in 50 mL petroleum
ether was magnetically stirred under a He atmosphere. To this there
was added 50 mL of a 1.6 M hexane solution of butyllithium, and the
exothermic reaction, which produced a granular precipitate, was
allowed to stir for 12 h. The mixture was cooled to 0 °C and there
was then added 7.5 g dimethyldisulfide. There was a heavy precipitate
formed, which tended to become lighter as the addition of the
disulfide neared completion. After 20 min additional stirring, the
reaction mixture was poured into H2O that contained some HCl. The
phases were separated and the aqueous phase extracted with 50 mL Et2O.
The organic phase and extract were combined, washed with dilute NaOH,
and then with H2O. After drying over anhydrous K2CO3, the solvent was
removed under vacuum and the residue distilled to give a fraction that
boiled at 75-85 °C at 0.3 mm/Hg and weighed 5.3 g. This was about 80%
pure 2,5-bis-(methylthio)toluene, with the remainder appearing to be
the monothiomethyl analogues. A completely pure product was best
obtained by a different, but considerably longer, procedure. This is
given here only in outline. The phenolic OH group of
3-methyl-4-(methylthio)phenol was converted to an SH group by the
thermal rearrangement of the N,N-dimethylthioncarbamate. The impure
thiophenol was liberated from the product N,N-dimethylthiolcarbamate
with NaOH treatment. The separation of the phenol/thiophenol mixture
was achieved by a H2O2 oxidation to produce the intermediate
3-methyl-4-methylthiophenyldisulfide. This was isolated as a white
crystalline solid from MeOH, with a mp of 78-79 °C. Anal. (C16H18S4)
C,H. It was reduced with zinc in acetic acid, and the resulting
thiophenol (a water-white liquid which was both spectroscopically and
microanalytically correct) was methylated with methyl iodide and KOH
in MeOH to give the desired product, 2,5-bis-(methylthio)toluene, free
of any contaminating mono-sulfur analogues.
A solution of 3.9 g of 2,5-bis-(methylthio)toluene in 20 mL acetic
acid was treated with a crystal of iodine followed by the addition of
3.5 g elemental bromine. This mixture was heated on the steam bath
for 1 h, which largely discharged the color and produced a copious
evolution of HBr. Cooling in an ice bath produced solids that were
removed by filtration. Recrystallization from IPA gave 1.9 g of
2,5-bis-(methylthio)-4-bromotoluene as a white crystalline solid with
a mp of 133-134 °C. Anal. (C9H11BrS2) C,H. An alternate synthesis of
this intermediate was achieved from 1,4-dibromobenzene which was
converted to the 1,4-bis-(methylthio)benzene (white crystals with a mp
of 83.5-84.5 °C) with sodium methylmercaptide in
hexamethylphosphoramide. This was dibrominated to
2,5-dibromo-1,4-bis-(methylthio)benzene in acetic acid (white
platelets from hexane melting at 195-199 °C). This, in Et2O solution,
reacted with BuLi to replace one of the bromine atoms with lithium,
and subsequent treatment with methyl iodide gave
2,5-bis-(methylthio)-4-bromotoluene as an off-white solid identical to
the above material (by TLC and IR) but with a broader mp range.
A solution of 2.4 g 2,5-bis-(methylthio)-4-bromotoluene in 100 mL
anhydrous Et2O, stirred magnetically and under a He atmosphere, was
treated with 10 mL of a 1.6 M solution of butyllithium in hexane.
After stirring for 10 min there was added 2.5 mL N-methylformanilide
which led to an exothermic reaction. After another 10 min stirring,
the reaction mixture was added to 100 mL dilute HCl, the phases were
separated, and the aqueous phase extracted with 2x50 mL Et2O. The
combined organic phase and extracts were dried over anhydrous K2CO3,
and the solvent removed under vacuum. The partially solid residue was
distilled at 140-150 °C at 0.2 mm/Hg to give a crystalline fraction
that, after recrystallization from 15 mL boiling IPA gave
2,5-bis-(methylthio)-4-methylbenzaldehyde as a yellow-brown solid
which weighed 1.1 g and had a mp of 107-109 °C. An analytical sample
from MeOH melted at 110-111 °C with an excellent IR and NMR. Anal.
(C10H12OS2) C,H. An alternate synthesis of this aldehyde employs the
2,5-bis-(methylthio)toluene described above. A CH2Cl2 solution of
this substituted toluene containing dichloromethyl methyl ether was
treated with anhydrous AlCl3, and the usual workup gave a distilled
fraction that spontaneously crystallized to the desired aldehyde but
in an overall yield of only 11% of theory.
To a solution of 0.5 g 2,5-bis-(methylthio)-4-methylbenzaldehyde in 15
mL nitroethane there was added 0.15 g anhydrous ammonium acetate and
the mixture was heated on the steam bath for 1 h. The excess solvent
was removed under vacuum and the residue was dissolved in 10 mL
boiling MeOH. This solution was decanted from a little insoluble
residue, and allowed to cool to ice bath temperature yielding, after
filtering and drying to constant weight, 0.55 g of
1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene as
pumpkin-colored crystals with a mp of 90-91 °C. This was not improved
by recrystallization from EtOH. Anal. (C12H15NO2S2) C,H.
A cooled, stirred solution of 0.5 g LAH in 40 mL THF was put under an
inert atmosphere, cooled to 0 °C with an external ice bath, and
treated with 0.42 mL 100% H2SO4, added dropwise. A solution of 0.5 g
1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene in 20 mL
anhydrous THF was added over the course of 5 min, and the reaction
mixture held at reflux for 30 min on the steam bath. After cooling
again to ice temperature, the excess hydride was destroyed by the
addition of IPA and the inorganics were converted to a loose, white
filterable form by the addition of 1.5 mL 5% NaOH. These solids were
removed by filtration and the filter cake was washed with 2x50 mL IPA.
The combined filtrate and washings were stripped of solvent under
vacuum to give a residue that was a flocculant solid. This was
suspended in dilute H2SO4 and extracted with 2x50 mL CH2Cl2, and the
combined organics extracted with 2x50 mL dilute H3PO4. The aqueous
extracts were made basic, and the product removed by extraction with
2x75 mL CH2Cl2. After removal of the solvent under vacuum, the
residue was distilled at 126-142 °C at 0.2 mm/Hg to give 0.2 g of
product which crystallized in the receiver. This was dissolved in 1.5
mL hot IPA, neutralized with 4 drops of concentrated HCl, and diluted
with 3 mL anhydrous Et2O to give, after filtering and air drying, 0.2
g. of 2,5-bis-(methylthio)-4-methylamphetamine hydrochloride (BIS-TOM)
as white crystals with a mp of 228-229 °C. Anal. (C12H20ClNS2) C,H.
DOSAGE: greater than 160 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 160 mg) I was vaguely aware of something
in the latter part of the afternoon. A suggestion of darting,
physically (when going to sleep), but nothing at the mental level.
This is as high as I will go.
EXTENSIONS AND COMMENTARY: It is reasonable, in retrospect, to accept
that BIS-TOM is not an active compound. The replacement of the
2-position oxygen of DOM with a sulfur atom (to give 2-TOM) dropped
the potency by a factor of 15x, and the replacement of the 5-position
oxygen with a sulfur atom (to give 5-TOM) dropped the potency by a
factor of about 10x. It would be a logical calculation that the
replacement of both oxygen atoms with sulfur might drop the potency by
a factor of 150x. So, with DOM being active at maybe 5 milligrams, a
logical prediction of the active level of BIS-TOM would be 750
milligrams. And maybe this would be the right level, but with the
hints of neurological disturbance that seemed to be there at 160 mg,
there was no desire to go up by a factor of five again. The rewards
would simply not be worth the risks.
The 2-carbon analogue, 2C-BIS-TOM, was prepared from the intermediate
aldehyde above, first by reaction with nitromethane to give the
nitrostyrene as tomato-colored crystals from EtOAc, mp 145-146 °C.
Anal. (C11H13NO2S2) C,H. This was reduced with AH to give
2,5-bis-(methylthio)-4-methylphenethylamine hydrochloride as
ivory-colored crystals with a mp of 273-277 °C.
Although there are many interesting psychedelic drugs with sulfur
atoms in them (the TOM's, the TOET's, the ALEPH's and all of the
2C-T's), there just aren't many that contain two sulfur atoms.
BIS-TOM bombed out, and 2C-BIS-TOM remains untried, but will probably
also fail, as the phenethylamines are rarely more potent than the
corresponding amphetamines. This leaves 2C-T-14 as the remaining
hope, and its synthesis is still underway.
Back]
]