EXTENSIONS AND COMMENTARY: This entire venture into the study of TOMSO
was an outgrowth of the extraordinary response that had been shown by one person to 5-TOM. There were two obvious approaches that might throw some light on the reason for this dramatic sensitivity. One would be to see if he was unusually capable of metabolizing sulfur-containing molecules, and the second would be to assume he was, and to try to guess just what product he had manu-factured with his liver.
The individual sensitivity question was addressed in a tidy and direct manner. Why not study a simple sulfur-containing model compound that would probably be metabolized only at the sulfur and that would itself probably be pharmacologically inactive in its own rights? Sounded OK
to me, so I made up a goodly supply of 4-tert-butyl thioanisole, which proved to be a gorgeous white crystalline solid. It seemed quite logical that this would be metabolized at the sulfur atom to produce either or both the sulfoxide and the sulfone. So I treated a methanol solution of this with a little hydrogen peroxide and distilled the neutral extracts at 100-115 !C at 0.2 mm/Hg to give the sulfoxide as a solid that melted at 76-77 !C from hexane: Anal. (C11H16OS) C,H. On the other hand, if a solution of the thioanisole in acetic acid containing hydrogen peroxide was heated on the steam bath for a few hours and then worked up, a new solid was isolated that proved to be the sulfone (a negative Fries-Vogt test). This was obtained as white crystals with a mp of 94-95 !C from aqueous methanol. Anal.
(C11H16SO2) C,H. And I found that these three compounds separated well from one another by GC, and that they could be extracted from urine. Everything was falling into place. My thought was to determine a safe (inactive) level of the parent thioanisole, and determine the distri-bution of metabolites in my urine, and then in the urine of several other people, and then finally in the urine of the person who was the intense reactor to 5-TOM. I found that there were no effects, either physical or psychological, at an oral dose of 60 milligrams of 4-tert-butyl-thioanisole. But then everything fell apart. There was not a detectable trace of anything, neither parent compound nor either of the potential metabolites, to be found in my urine. The material was obviously being completely converted to one or more metabolites, but the sulfoxide and sulfone were not among them. It would be fun, someday, to methodically trace the fate of this compound.
So, on to the second approach. What might the active metabolite of 5-TOM actually be? The sulfoxide seemed completely reasonable, and that encouraged the synthesis of TOMSO. This name was given, as it is the sulfoxide analogue (SO) of 5-TOM. And since only one of these analogues has been made, the R5S distinction is not needed. But it is apparent that this approach to the finding of an explanation for the idiosyncratic sensitivity to 5-TOM also failed, in that TOMSO itself appeared to be without activity.
But the fallout of this study was the uncovering of an unusual property that alcohol can occasionally have when it follows the ingestion of certain inactive drugs. Or if it is used at the tail end of an experience with an active drug. Usually some alcohol has been employed as a softener of the residual effects of the dayUs experiment, or as a social habit to accompany the post-mortem discussions of a day's experiences, and perhaps as a help to sleeping.
But if there is a rekindling of the effect, rather than the sedation expected, then the verb Rto tomsoS can be used in the notes. It represents the promotion of an inactive situation into an active one, with the catalysis of alcohol. But the effect is not that of alcohol.
Might the extreme sensitivity of some alcoholics to even a small amount of alcohol be due to some endogenous RinactiveS factor that is promoted in this way into some centrally florid toxicity? I remember seeing proposals of some tetrahydroisoquinolines as potential mis-metabolites in efforts to explain the toxicity of alcohol. Maybe they are nothing more than psychedelics that are thought to be inactive, but which might be ignited with a glass of wine. And the person is tomsoing with his small amount of alcohol.
174 TP; THIOPROSCALINE; 3,5-DIMETHOXY-4-(n)-PROPYLTHIOPHENETHYLAMINE
SYNTHESIS: A solution was made of 12.1 g N,N,NU,NU-tetramethylethylenediamine and 13.8 g of 1,3-dimethoxybenzene in 200 mL 30-60 !C petroleum ether. This was stirred vigorously under a He atmosphere and cooled to 0 !C with an external ice bath. There was added 66 mL of 1.6 M butyllithium in hexane which produced a white granular precipitate. The reaction mixture was brought up to room temperature for a few minutes, and then cooled again to 0 !C. There was then added 15.8 g of di-(n)-propyl disulfide which changed the granular precipitate to a creamy appearance. Stirring was continued while the reaction mixture was brought up to room temperature and finally up to reflux. The reaction mixture was then added to 600 mL of dilute H2SO4. The two phases were separated, and the aqueous phase extracted with 2x75 mL Et2O. The organic phases were combined, and the solvent removed under vacuum.
The residue was 24.2 g of a pale amber liquid which was distilled at 0.35 mm/Hg to give two fractions. The first boiled at 85-90 !C, weighed 0.5 g and appeared to be recovered dipropyl disulfide. The product 2-(n)-propylthio-1,3-dimethoxybenzene boiled at at 105-125 !C, and weighed 20.8 g. A small sample recrystallized from hexane had a mp of 27-28 !C. Anal. (C11H16O2S) C,H.
To a stirred solution of 19.8 g of
2-(n)-propylthio-1,3-dimethoxybenzene in 200 mL CH2Cl2 there was added 15.4 g elemental bromine dissolved in 100 mL CH2Cl2. The reaction was not exothermic, and it was allowed to stir for 1 h. The reaction mixture was washed with H2O containing sodium hydrosulfite (which rendered it nearly colorless) and finally washed with saturated brine.
The solvent was removed under vacuum leaving 33.5 g of a pale yellow liquid. This was distilled at 112-120 !C at 0.3 mm/Hg to yield 4-bromo-2-(n)-propylthio-1,3-dimethoxybenzene as a pale yellow oil.
Anal. (C11H15BrO2S) C,H.
To a solution of 16.8 g diisopropylamine in 100 mL anhydrous THF that was stirred under a N2 atmosphere and cooled to -10 !C with an external ice/MeOH bath, there was added in sequence 75 mL of 1.6 M
butyllithium in hexane, 3.0 mL of dry CH3CN, and 8.7 g of 4-bromo-2-(n)-propylthio-1,3-dimethoxybenzene which had been dissolved in 20 mL THF. The bromo compound was added dropwise over the course of 5 min. The color became deep red-brown. Stirring was maintained for a total of 30 min while the reaction came to room temperature. It was then poured into 750 mL dilute H2SO4, the organic layer separated, and the aqueous phase extracted with 2x100 mL CH2Cl2. These extracts were pooled, washed with dilute H2SO4, and the solvent was removed under vacuum yielding a residue that was distilled. Two distillation cuts were taken at 0.3 mm/Hg. The first fraction boiled at 110-138 !C
and weighed 0.7 g and was discarded. The second fraction came over at 148-178 !C and weighed 3.0 g. By thin layer chromatography this fraction was about 80% pure, and was used as such in the following reduction. A small sample was ground under methyl cyclopentane yielding white crystals of
3,5-dimethoxy-4-(n)-propylthiophenylacetonitrile with a mp of 35.5-37.5 !C.
A solution of LAH in THF (15 mL of a 1 M solution) under N2 was cooled to 0 !C and vigorously stirred. There was added, dropwise, 0.4 mL
100% H2SO4, followed by 2.7 g
3,5-dimethoxy-4-(n)-propylthiophenylacetonitrile dissolved in 10 mL
anhydrous THF. The reaction mixture was stirred at 0 !C for a few min, then brought to a reflux for 30 min on the steam bath. After cooling back to room temperature, there was added IPA to destroy the excess hydride and 10% NaOH to bring the reaction to a basic pH and converted the aluminum oxide to a loose, white, filterable consistency. This was removed by filtration and washed with both THF
and IPA. The filtrate and washes were stripped of solvent under vacuum, the residue added to 1 L dilute H2SO4. This was washed with 2x75 mL CH2Cl2, made basic with aqueous NaOH, extracted with 3x75 mL
CH2Cl2, the extracts pooled, and the solvent removed under vacuum.
The residue was distilled at 137-157 !C at 0.3 mm/Hg to give 1.3 g of a colorless oil. This was dissolved in 10
mL of IPA, neutralized with 20 drops of concentrated HCl and, with continuous stirring, diluted with 50 mL anhydrous Et2O. The product was removed by filtration, washed with Et2O, and air dried to give 1.4 g of 3,5-dimethoxy-4-(n)-propylthiophenethylamine hydrochloride (TP) as bright white crystals with a mp of 164-165 !C. Anal. (C13H22ClNO2S) C,H.
DOSAGE: 20 - 25 mg.
DURATION: 10 - 15 h.
QUALITATIVE COMMENTS: (with 18 mg) There was very little effect until more than two hours, when I came inside out of the cold and jumped to an immediate +1. It is hard to define, and I am quite willing to have it develop more, and if not, quite willing to go higher next time. I got into several quite technical conversations, but through it all I was aware of a continuous alteration. There was a drop at the seventh hour, and nothing at all was left at twelve hours.
(with 27 mg) My body feels heavy. This is not a negative thing, but it is there. I feel a heavy pressure at the back of the neck, which is probably unresolved energy. The nervous system seems to be somehow vunerable. Towards the end of the experience I considered a Miltown, but settled on an aspirin, and I still couldnUt sleep for about 24
hours. The imagery is extremely rich and there is quite a bit of eyes-open visual, but mostly eyes closed. I think the rewards are not worth the body price. Sometime again, maybe lower?S
EXTENSIONS AND COMMENTARY: There is a high potency here, but clearly there are signs of increased toxicity as well even over the ethyl homologue, TE. The butyl compound (see TB) was the last of this series of phenethylamines and as is noted there, the physical problems lessen, but so do the psychedelic properties. The three-carbon amphetamine homologues are completely unexplored. The most reasonable starting material for these would be 4-thiosyringaldehyde, with S-alkylation and then the conventional nitroethane coupling followed with LAH reduction. The most appealing target as a potential psychedelic would be the methylthio homologue (3,5-dimethoxy-4-methylthioamphetamine, 3C-TM) or, as a potential euphoriant, the butylthio homologue
(3,5-dimethoxy-4-(n)-butylthioamphetamine, 3C-TB). I am not sure that these alkylthio analogues would justify the labor needed to make them.
175 TRIS; TRESCALINE; TRISESCALINE; 3,4,5-TRIETHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 16.9 g of ethyl 3,4,5-triethoxybenzoate in 25
mL THF was added to a well stirred suspension of 8 g LAH in 150 mL
THF. The mixture was heated at reflux for 24 h and and, after cooling, treated with IPA to destroy the excess hydride. There was then added sufficient 25% NaOH to produce a granular, white form of the aluminum oxide. This was removed by filtration, the filter cake washed with IPA, and the filtrate and washes were combined and stripped of solvent under vacuum. The residue weighed 12.2 g and was distilled at 120-140 !C at 0.4 mm/Hg to yield 8.6 g of 3,4,5-triethoxybenzyl alcohol that spontaneously crystallized. It had a mp of 29-30 !C and was free of the parent ester carbonyl absorp-tion at 1709 cm-1 in the infra-red.
This product 3,4,5-triethoxybenzyl alcohol was suspended in 30 mL
con-centrated HCl, heated briefly on the steam bath, cooled to room temperature, and suspended in a mixture of 75 mL CH2Cl2 and 75 mL H2O.
The phases were separated, and the aqueous phase extracted with another 75 mL CH2Cl2. The organic fractions were combined, washed first with H2O and then with saturated brine. Removal of the solvent under vacuum yielded an off-white oil that was distilled at 112-125 !C
at 0.4 mm/Hg to provide 7.5 g of 3,4,5-triethoxybenzyl chloride that spontaneously crystallized. The crude product had a mp of 34-37 !C
which was increased to 37.5-38.5 !C upon recrystallization from hexane. Anal. (C13H19ClO3) C,H.
A solution of 4.5 g 3,4,5-triethoxybenzyl chloride in 10 mL DMF was treated with 5.0 g sodium cyanide and heated for 1 h on the steam bath. The mixture was then poured into 100 mL H2O and the oily phase that resulted immediately crystallized. This was filtered off, washed well with H2O, air dried, and distilled at 128-140 !C at 0.25 mm/Hg to yield 3.7 g of 3,4,5-triethoxyphenylacetonitrile which melted at 54-56.5 !C. There was a sharp nitrile band at 2249 cm-1. Anal.
(C14H19NO3) C,H.
To 18.8 mL of a 1 M solution of LAH in THF under N2 , vigorously stirred and cooled to 0 !C, there was added, dropwise, 0.50 mL 100%
H2SO4. This was followed by 3.6 g 3,4,5-triethoxyphenylacetonitrile in 10 mL anhydrous THF over the course of 5 min. The reaction mixture was brought to room temperature and stirred for a few min, and finally held at reflux on the steam bath for 1 h. After cooling back to room temperature, there was added about 2 mL IPA (to destroy the excess hydride) followed by sufficient 15% NaOH to make the aluminum oxide granular and white, and the organic solution basic. The solids were removed by filtration, and washed with IPA. The filtrate and washes were stripped of solvent under vacuum, the residue added to 400 mL
dilute H2SO4. This was washed with 2x75 mL CH2Cl2, the aqueous phase made basic with aqueous. NaOH, and the product extracted with 2x75 mL
CH2Cl2. These extracts were pooled, the solvent removed under vacuum, and the residue distilled at 115-135 !C at 0.4 mm/Hg to give a white oil. This was dissolved in a few mL of IPA, neutralized with concentrated HCl, and diluted with anhydrous Et2O to the point of turbidity. When the crystal formation was complete, the product was removed by filtration, washed with Et2O, and air dried to give 2.8 g 3,4,5-triethoxyphenethylamine hydrochloride (TRIS) as white crystals with a mp of 177-178 !C.
DOSAGE: greater than 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 240 mg) No effects were noted at any time following 240 milligrams of trisescaline. This would have been a thoroughly active level of the trimethoxy counterpart, mescaline.
EXTENSIONS AND COMMENTARY: With the progressive diminution of human potency with increased ethylation of the mescaline molecule, there is no suprise in finding that this base is devoid of activity. Studies done years ago in the cat at a dosage of 25 mg/Kg (i.m.) gave none of the expected, and looked for, signs of behavioral changes (pilomotor activity, pupillary dilation, growling, hissing, aggressive behavior, withdrawal, or salivation) that are often seen with the less bulky substituents. It was without action.
More lengthy substituents in the 3,4,5-positions (with combinations of ethyls and propyls, for example) are presently unknown compounds, and there is small incentive to make them.
176 3-TSB; 3-THIOSYMBESCALINE;
3-ETHOXY-5-ETHYLTHIO-4-METHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 13.4 g
3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzylidenimine (see under ME
for its preparation) in 150 mL anhydrous Et2O was placed in a He atmosphere, well stirred, and cooled in an external dry ice/acetone bath to -80 !C. There was the formation of a granular precipitate.
There was then added 28 mL of 1.6 N butyllithium in hexane over the course of 5 min, and the mixture (which had turned quite creamy) was stirred for 15 min. This was followed by the addition of 5.5 g diethyl disulfide over the course of 1 min. The mixture was allowed to come to room temperature over the course of 1 h, and then added to 100 mL of dilute HCl. The Et2O phase was separated and the solvent removed under vacuum. The residue was dissolved in 50 mL MeOH, combined with the original aqueous phase, and the entire mixture heated on the steam bath for 0.5 h. The aqueous solution was cooled to room temperature, extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was distilled at 132-140 !C at 0.3 mm/Hg to yield 9.1 g of 3-ethoxy-5-ethylthio-4-methoxybenzaldehyde as a white oil that, on standing for several months, spontaneously crystallized. A small bit of the crystalline solid was wastefully recrystallized from MeOH to provide white crystals with a mp of 31.5-32.5 !C. Anal. (C12H16O3S) C,H. The crude distillate was used in the following reactions.
Several attempts were made to prepare the nitrostyrene from this aldehyde and nitromethane. The most successful, but still inadequate, procedure is described here. A solution of 1.0 g 3-ethoxy-5-ethylthio-4-methoxybenzaldehyd
e in 10 mL nitromethane was treated with about 150 mg of anhydrous ammonium acetate and heated on the steam bath. The course of the reaction was followed by TLC. The bulk of the aldehyde had disappeared in 45 min, and there were several UV-absorbing spots visible. Removal of the excess nitromethane under vacuum gave an orange oil which, when rubbed under cold MeOH, gave 200
mg of yellow solids. This was (by TLC) a mixture of nitrostyrene, starting aldehyde, and several slow-moving scrudge impurities.
Recrystallization from MeOH gave a poor recovery of a yellow solid with a mp of 102.5-104 !C but this was still contaminated with the same impurities. Several repetitions of this synthetic procedure gave little if any of the desired
3-ethoxy-5-ethylthio-4-methoxy-'-nitrostyrene.
A suspension of 5.4 g methyltriphenylphosphonium bromide in 30 mL
anhydrous THF was placed under a He atmosphere, well stirred, and cooled with an external water bath. There was then added 10 mL of 1.6
N butyllithium in hexane which resulted in the generation of a bright pumpkin color. The initial heavy solids changed into a granular precipitate. There was then added 2.4 g of 3-ethoxy-5-ethylthio-4-methoxybenzaldehyde in a little THF. An initial gummy phase became granular with patient swirling and stirring. After 30 min, the reaction was quenched in 500 mL H2O, the top hexane layer separated, and the aqueous phase extracted with 2x75
mL of petroleum ether. The organic fractions were combined, washed with H2O, dried over anhydrous K2CO3, and the solvents removed under vacuum to give the crude 3-ethoxy-5-ethylthio-4-methoxystyrene as a yellow mobile liquid.
A solution of 2 mL of borane-methyl sulfide complex (10 M BH3 in methyl sulfide) in 20 mL THF was placed in a He atmosphere, cooled to 0 !C, treated with 4.2 mL of 2-methylbutene, and stirred for 1 h while returning to room temperature. To this there was added a solution of the impure 3-ethoxy-5-ethylthio-4-methoxystyrene in a little anhydrous THF. This was stirred for 1 h. The excess borane was destroyed with 1 mL MeOH, followed by the addition of 3.8 g elemental iodine, followed in turn by a solution of 0.8 g NaOH in hot MeOH added over the course of 5 min. The color gradually faded, and became a pale lime green. This was added to 300 mL dilute aqueous sodium thiosulfate which was extracted with 2x100 mL petroleum ether. The extracts were pooled, and the solvent evaporated under vacuum to provide crude 1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-iodoethane as a residue.
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