2-methoxy-3-methyl-5-(methylthio)benzaldehyde, which was best separated by preparative gas chromatography. The proof of the structure of the major aldehyde above was obtained by its reductive conversion to 2,5-dimethyl-4-(methylthio)anisole with amalgamated zinc and HCl. The details are given in the recipe for 5-TOM.
To 4 mL glacial acetic acid there was added 1.0 g 5-methoxy-4-methyl-2-(methylthio)benzaldehyde, 0.35 g anhydrous ammonium acetate, and 0.8 g nitroethane, and the mixture was heated on the steam bath for 4 h. Another 0.5 g of nitroethane was added, and the heating continued for an additional 4 h. Standing at room temperature overnight allowed the deposition of spectacular orange crystals which were removed by filtration, washed lightly with acetic acid, and air dried. This product melted at 82-83 !C.
Recrystallization from 10 mL boiling MeOH gave 0.7 g of 1-(5-methoxy-4-methyl-2-methylthiophenyl)-2-nitropropene with a mp of 83-84 !C. Anal. (C12H15NO3S) C,H. The alternate method for the formation of nitrostyrenes, the reaction of the benzaldehyde in nitroethane as both reagent and solvent, with ammonium acetate as a catalyst, gave a gummy product that could be purified only with severe losses. The overall yield with this latter method was 24% of theory.
A solution of 1.5 g LAH in 75 mL THF was cooled, under He, to 0 !C
with an external ice bath. With good stirring there was added 1.0 mL
100% H2SO4 drop-wise, to minimize charring. This was followed by the addition of 3.0 g
1-(5-methoxy-4-methyl-2-methylthiophenyl)-2-nitropropene in 20 mL
anhydrous THF. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath, and then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of IPA followed by sufficient 5% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic. 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 providing a light yellow oil.
This was dissolved in 100 mL dilute H2SO4 and then washed with 2x50 mL
CH2Cl2. The aqueous phase was made basic with 5% NaOH and extracted with 2x50 mL CH2Cl2. These were pooled, the solvent removed under vacuum, and the residue distilled at 105-130 !C at 0.25 mm/Hg to give 1.6 g of a white oil. This was dissolved in 8 mL IPA, neutralized with 24 drops of concentrated HCl which formed crystals spontaneously.
Another 20 mL of hot IPA was added to effect complete solution, and then this was diluted with anhydrous Et2O. On cooling fine white crystals of 5-methoxy-4-methyl-2-methylthioamphetamine hydrochloride (2-TOM) separated. These weighed 1.55 g and had a mp of 195-196 !C.
Anal. (C12H20ClNOS) C,H.
DOSAGE: 60 - 100 mg.
DURATION: 8 - 10 h.
QUALITATIVE COMMENTS: (with 60 mg) There is a superb body feeling, and food tasted excellent but then it just might have been excellent food. By the tenth hour, there were absolutely no residues, and I had the feeling that there was no price to pay. Venture up a bit with confidence.
(with 80 mg) For me this was excellent, in a down-to-earth, humorous, matter-of-fact universe-perspective sense. Very pleasant feeling, although there was a strong body awareness below the waist (not the erotic thing, but rather a slight heaviness, and the next day I came down with a G.I. cold). Very good feeling, and I sense that the depth of the experience is way out there where the big questions lie. I found it easy to go out of body (in the good sense) into a warm, loving darkness. Sliding down by 6, 7th hour, and had no trouble sleeping. Fully scripted dreams, vivid. Very, very good. Want to try 100 mg.
(with 80 mg) Completely foul taste. The effects were quite subtle, and I found this to be a strange but friendly ++. There was much eyes-closed fantasizing to music, even to Bruchner, whom I found unexpectedly pleasant. There was a feeling of tenseness at the twilight of the experience.
EXTENSIONS AND COMMENTARY: There is a most extraordinary loss of potency with the simple substitution of a sulfur atom for an oxygen atom. DOM is fully active at the 5 or so milligram area, whereas 2-TOM is active at maybe the 80 milligram area, a loss of potency by a factor of x15 or so. And the duration is quite a bit shorter. It might take a fair amount of learning to become completely at peace with it, but it might be worth the effort. And there are none of the disturbing hints of neurological and physical roughness of 5-TOM.
Again, as with the other TOM's and TOETUs, the two-carbon homologue of this has been synthesized but not yet evaluated. The common intermediate benzaldehyde,
5-methoxy-4-methyl-2-(methylthio)benzaldehyde was condensed with nitromethane and ammonium acetate to give the nitrostyrene which, upon re-crystallization from ethanol, had a melting point of 118-118.5 !C.
Anal. (C11H13NO3S) C,H. Reduction with aluminum hydride in THF gave the crystalline free base which, as the hydrochloride salt, melted at 233-234 !C. Anal. (C11H18ClNOS) C,H. Quite logically, it has been called 2C-2-TOM.
172 5-TOM; 2-METHOXY-4-METHYL-5-METHYLTHIOAMPHETAMINE
SYNTHESIS: To a solution of 6.6 g KOH pellets in 100 mL hot EtOH there was added a solution of 15.4 g methylthio-m-cresol (3-methyl-4-(methylthio)phenol, Crown-Zellerbach Corporation) in 25 mL
EtOH. This was followed by the addition of 17 g methyl iodide, and the mixture was held at reflux on the steam bath for 16 h. The reaction mixture was poured into 400 mL H2O, acidified with HCl, and extracted with 4x50 mL CH2Cl2. These were pooled, washed with 3x50 mL
5% NaOH, once with dilute HCl, and then the solvent was removed under vacuum. The residue was 3-methyl-4-(methylthio)anisole, a clear pale yellow oil, weighing 12.7 g. Distillation at 150-160 !C at 1.7 mm/Hg, or at 80-90 !C at 0.25 mm/Hg, did not remove the color, and gave a product with no improvement in purity.
To a mixture of 82 g POCl3 and 72 g N-methylformanilide that had been heated on the steam bath for 10 min, there was added 33.6 g 3-methyl-4-(methylthio)phenol, and heating was continued for an additional 2 h. This was poured into 1.2 L H2O, producing a brown gummy crystalline mass that slowly loosened on continued stirring.
This was filtered off, washed with additional H2O, and sucked as dry as possible. This was finely ground under 60 mL of cold MeOH, refiltered, and air dried to give 17.8 g of a nearly white crystalline solid with a mp of 94-96 !C. Recrystallization from 50 mL boiling MeOH gave a product of higher purity, but at some cost in yield. With this step there was obtained 13.4 g of 2-methoxy-4-methyl-5-(methylthio)benzaldehyde with a mp of 98-99 !C.
An additional recrystallization from IPA increased this mp by another degree. From this final recrystallization, a small amount of material was left as an insoluble residue. It was also insoluble in acetone, but dissolved readily in CH2Cl2. It melted broadly at about 200 !C
and was not identified. Proof of the structure of 2-methoxy-4-methyl-5-(methylthio)benzaldehyde was obtained by its successful reduction (with amalgamated Zn in HCl) to 2,5-dimethyl-4-(methylthio)anisole. This reference convergence compound was prepared separately from 2,5-dimethylanisole which reacted with chlorosulfonic acid to give the 4-sulfonyl chloride derivative, which was in turn reduced to the 4-mercapto derivative (white crystals from MeOH, with a mp of 38 !C sharp). This, upon methylation with methyl iodide and KOH in MeOH, gave 2,5-dimethoxy-4-(methylthio)anisole (white crystals from MeOH, with a mp of 67-68 !C). The two samples (one from the aldehyde reduction, and the other from this independent synthesis), were identical in all respects.
A solution of 1.9 g 2-methoxy-4-methyl-5-(methylthio)benzaldehyde in 40 mL nitroethane was treated with 0.5 g anhydrous ammonium acetate and heated under reflux, with stirring, with a heating mantle for 3.5
h, at which time TLC analysis showed no unreacted aldehyde and only a trace of slow moving materials. Removal of the excess nitroethane under vacuum gave a yellow plastic film (the wrapping of the magnetic stirrer had dissolved off) which was extracted first with 35 mL
boiling MeOH, then with 2x35 mL boiling IPA. Separately, the MeOH
extract and the combined
IPA extracts, on cooling, deposited 0.6 g each of fluffy needles. The mother liquors were combined and allowed to evaporate to about 15 mL final volume, providing another 0.4 g crude product. All three samples melted at 101-102 !C. These were combined, and recrystallized from 50 mL boiling MeOH to provide, after filtering and air drying, 1.4 g of
1-(2-methoxy-4-methyl-5-methyl-thiophenyl)-2-nitropropene as bright yellow crystals with a mp of 102-102.5 !C. Anal. (C12H15NO3S) C,H.
A solution of 2.0 g LAH in 100 mL anhydrous THF was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 1.28 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 1.35 g
1-(2-methoxy-4-methyl-5-methylthiophenyl)-2-nitropropene in 50 mL
anhydrous THF over the course of 5 min. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath, and then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of 5 mL IPA followed by sufficient 5% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic (about 5 mL was used). The reaction mixture was filtered, and the filter cake washed first with THF and then with IPA. The combined filtrate and washings were stripped of solvent under vacuum and the residue dissolved in 150
mL dilute H2SO4. This was washed with 3x50 mL CH2Cl2 (the color stayed in the organic layer), made basic with aqueous NaOH, and extracted with 2x50 mL CH2Cl2. After the solvent was removed under vacuum, the residue was distilled at 110-125 !C at 0.4 mm/Hg to give 0.9 g of a colorless oil. This was dissolved in 4 mL IPA, neutralized with about 11 drops of concentrated HCl, and then diluted with 20 mL
anhydrous Et2O. After about a ten second delay, white crystals formed. These were removed by filtration and air dried, to give 0.6 g of 2-methoxy-4-methyl-5-methylthioamphetamine hydrochloride (5-TOM) as white crystals with a mp of 156-157 !C. A second crop obtained from the mother liquors on standing weighed 0.3 g and melted at 150-156 !C.
Anal. (C12H20ClNOS) C,H.
DOSAGE: 30 - 50 mg.
DURATION: 6 - 10 h.
QUALITATIVE COMMENTS: (with 35 mg) There was an awful lot of visual activity, and in general I found the day quite good, once I got past the early discomfort.
(with 40 mg) I knew that I was sinking into a deep reverie after an hour into it. I was not totally unconscious since I seemed to respond to external stimuli (at least most of the time). But I certainly wasnUt all that much there. The exper-ience dominated completely. At one point (perhaps the peak?) I remember seeing a very quiet sea with a horizontal shoreline and a clear sky. This image seemed to come back rather frequently. At other times I would see a set of disjointed horizontal lines on this beach. These lines reminded me of spectral lines. For a short period of time I thought they were some kind of expression of my energy levels that I didnUt understand. In retrospect, I suspect the horizontal lines were only expressions of how my mind was reacting to the material. I donUt remember talking to anyone until I had started to come down from the experience. I eventually could see real images, but they were greatly distorted. It was as if I was looking at Cubism paintings by Picasso, having intense and strange colorations. As I came back into the real world, I realized that I had had an extraordinary trip. I had not been afraid at any time. The experience seemed unique, but quite benign. The experience for my fellow travelers was probably much more anxious. I wasnUt particularly interested in food when I came down. I slept well. I was quite lethargic the next day. It really took me another day to integrate back into normal life. Would I repeat it? Possibly, but at a way smaller dose.
(with 50 mg) The body was complete whacked, and the mental simply didnUt keep up with it. There was some early nausea going into it, and my sinuses never cleared, and I somehow became irritable and angry. In fact, the impatience and grimness lasted for a couple of days. There were some visual events that might have been interesting to explore, but too much other stuff got in the way.
(with 50 mg) There was much eyes-closed fantasy, and quite a bit of it with erotic undertones. In efforts to direct my actions, I found it difficult to find the point of initiation of a task. Reading and writing both impossible. I am somehow de-focused. But art work became quite rewarding. The experience was heavy going in, but rich coming out. Good dosage.
EXTENSIONS AND COMMENTARY: The bottom line is that 5-TOM is a pretty heavy-duty experience, with more negative reports than positive ones.
I have received no mentions of a completely ecstatic time, and not even very many neutral experiences. The consensus is that it wasnUt worth the struggle. Some cramping, some nausea, and a generalized discomfort. And that one case of a catatonic response. An approach to possible individual variation in the metabolic handling of the sulfur atom is the rationale for the preparation of the compound TOMSO, and it is discussed there.
The two-carbon homologue of 5-TOM has been prepared. It uses, of course, the same aldehyde, but the condensation was with nitromethane which yielded the nitrostyrene as an orange powder with a melting point of 118-119 !C from methanol. This was reduced with LAH in ether containing anhydrous AlCl3, giving
2-methoxy-4-methyl-5-methylthiophenethylamine hydrochloride as white crystals with a melting point of 257-258 !C. It has been named 2C-5-TOM, but it has not yet been entered into the screening program so it is pharmacologically still a mystery.
173 TOMSO; 2-METHOXY-4-METHYL-5-METHYLSULFINYLAMPHETAMINE
SYNTHESIS: A suspension of 12.7 g
1-(2-methoxy-4-methyl-5-methylthiophenyl)-2-nitropropene (see under 5-TOM for its preparation) in 50 mL warm acetic acid was added to a suspension of 22.5 g electrolytic grade elemental iron in 100 mL warm acetic acid. The temperature was raised cautiously until an exothermic reaction set in, and the mixture was maintained under reflux conditions as the color progressed from yellow to deep brown to eventually colorless. After coming back to room temperature, the somewhat gummy mixture was poured into 1 L H2O, and all insolubles were removed by filtration. These were washed with CH2Cl2, and the aqueous filtrate was extracted with 3x100 mL CH2Cl2. The washes and extracts were combined, washed with 5% NaOH until the bulk of the color was removed and the washes remained basic, and the solvent was then removed under vacuum. The residue, 11.6 g of a pale amber oil that crystallized, was distilled at 110-120 !C at 0.4 mm/Hg to give 9.9 g 2-methoxy-4-methyl-5-methylthiophenylacetone with a mp of 41-42
!C. This was not im-proved by recrystallization from hexane. Anal.
(C12H16O2S) C,H.
To a solution of 7.3 g 2-methoxy-4-methyl-5-methylthiophenylacetone in 35 mL methanol there was added 7.3 mL 35% hydrogen peroxide, and the mixture held under reflux conditions for 40 min. All volatiles were removed under vacuum, and the residue suspended in 250 mL H2O. This was extracted with 3x50 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue, 8.6 g of an oily solid, was recrystallized from 10 mL boiling toluene to provide, after filtering and air drying, 5.4 g of
2-methoxy-4-methyl-5-methylsulfinylphenylacetone as a white solid with a mp of 89-89.5 !C. Anal. (C12H16O3S) C,H.
To a vigorously stirred solution of 5.2 g of 2-methoxy-4-methyl-5-methylsulfinylphenylacetone in 70 mL MeOH there was added 17 g anhydrous ammonium acetate followed by 1.0 g sodium cyanoborohydride. HCl was added as needed to maintain the pH at about 6 as determined with damp universal pH paper. No further base was generated after 3 days, and the reaction mixture was poured into 500
mL H2O. After acidification with HCl (caution, highly poisonous HCN
is evolved), this was washed with 2x100 mL CH2Cl2, made strongly basic with NaOH, and then extracted with 3x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the residue weighed 7.1 g and was a pale amber oil. This was distilled at 150-160
!C at 0.3 mm/Hg to give a colorless oil weighing 4.4 g. A solution of this in 13 mL IPA was neutralized with 30 drops of concentrated HCl and the resulting solution warmed and diluted with 20 mL of
warm anhydrous Et2O. White crystals separated immediately and, after filtering, ether washing and air drying, provided 4.4 g of 2-methoxy-4-methyl-5-methylsulfinylamphetamine hydrochloride (TOMSO) that melted at 227-229 !C after vacuum drying for 24 hrs. Anal.
(C12H20ClNO2S) C,H. The presence of two chiral centers (the alpha-carbon of the amphetamine side chain and the sulfoxide group at the 5-position of the ring) dictates that this product was a mixture of diastereoisomeric racemic compounds. No effort was made to separate them.
DOSAGE: greater than 150 mg (alone) or 100 - 150 mg (with alcohol).
DURATION: 10 - 16 h.
QUALITATIVE COMMENTS: (with 100 mg) There were no effects at all, and it was at the so-called surprise pot-luck birthday lunch for the department chairman that I ate a little and had two glasses of Zinfandel. I shot up to an immediate ++ and this lasted all afternoon. I went to San Francisco by BART, and walked up Market Street and saw all the completely bizarre faces. I was absolutely unable to estimate the age of anybody who was female, at least by looking at her face. All aspects, both child-like and old, seemed to be amalgamated into each face, all at the same time. There was remarkable time-slowing; overall the experience was favorable. That certainly was not the effect of the alcohol in the wine. Food poisoning? No. It must have been the TOMSO that had been kindled and promoted to something.
(with 150 mg) At best there is a threshold and it is going nowhere.
At the third hour I drank, over the course of an hour, a tall drink containing 3 oz. of vodka. Soon I was clearly somewhere, and three hours later I was a rolling plus three. This lasted until well after midnight, and was not an alcohol response.
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