PiHKAL: The Chemical Story 13
#169 2-TOET; 4-ETHYL-5-METHOXY-2-METHYLTHIOAMPHETAMINE
SYNTHESIS: A mixture of 24.4 g ortho-ethylphenol and 18.9 mL methyl iodide was added to a solution of 15.6 g 85% KOH in 100 mL hot MeOH. The mixture was kept at reflux temperature overnight, stripped as much as possible of the MeOH, and poured into 1 L H2O. An excess of 5% NaOH was added and this was extracted with 3x75 mL CH2Cl2. The pooled extracts were washed with 1% NaOH, and the solvent removed under vacuum to give 32.8 g of a pale amber oil. This was distilled at 55-65 °C at 0.4 mm/Hg to yield 22.0 g of 2-ethylanisole as a colorless oil.
To a 21.7 g sample of 2-ethylanisole, well stirred but without solvent, there was added, 1 mL at a time, 21 mL of chlorosulfonic acid. The color progressed from white to yellow, and finally to deep purple, with the evolution of much HCl. The exothermic reaction mixture was allowed to stir until it had returned to room temperature (about 0.5 h). It was then poured over 400 mL cracked ice with good mechanical stirring, which produced a mass of pale pink solids. These were removed by filtration, washed well with H2O, and air dried to give about 27 g of 3-ethyl-4-methoxybenzenesulfonyl chloride as an off-white solid that retained some H2O. A sample recrystallized from cyclohexane had a mp of 44-46 °C. A sample treated with ammonium hydroxide provided white crystals of 3-ethyl-4-methoxybenzenesulfonamide which could be recrystallized from H2O to give tufts of crystals with a mp of 97-98 °C. Anal. (C9H13NO3S) C,H.
In a 2 L round bottomed flask equipped with a mechanical stirrer there was added 200 mL cracked ice, 45 mL of concentrated H2SO4, 26.7 g of still moist 3-ethyl-4-methoxybenzenesulfonyl chloride, and 45 g elemental zinc dust. With external heating, an exothermic reaction set in and the temperature was maintained at reflux conditions for 4 h. After cooling to room temperature, the reaction mixture was filtered and the insolubles washed alternately with H2O and with CH2Cl2. The mother liquors and washings were diluted with sufficient H2O to allow CH2Cl2 to become the lower phase. These phases were separated, and the aqueous phase extracted with 3x100 mL CH2Cl2. The original organic phase and the extracts were pooled, washed with H2O, and the solvent removed to give 15.7 g of a smelly amber oil. This was distilled at 72-84 °C at 0.3 mm/Hg to give 12.1 g of 3-ethyl-4-methoxythiophenol as a water-white oil. The infra-red was perfect (with the SH stretch at 2562, OCH3 at 2837 and 1061, and with fingerprint peaks at 806, 880, 1052, (1061), 1142 and 1179 cm-1). Anal. (C9H12OS) C,H.
To a solution of 11.7 g of 3-ethyl-4-methoxythiophenol and 6.5 mL methyl iodide in 100 mL MeOH there was added, with good stirring and a bit at a time, a solution of 5.5 g 85% KOH in 25 mL hot MeOH. The mixture was held at reflux on the steam bath for 1.5 h, and then stripped of volatiles under vacuum. The residues were added to 400 mL H2O, made strongly basic with 5% NaOH, and extracted with 3x75 mL CH2Cl2. The pooled extracts were back-washed with 1% NaOH, and the solvent removed under vacuum. The 13.2 g residue was distilled giving 2-ethyl-4-(methylthio)anisole as a fraction boiling at 78-85 °C at 0.2 mm/Hg. The weight was 11.6 g for an isolated yield of over 90% of theory. The mp was at about 0 °C. The infra-red showed no SH or other functionality, but an OCH3 at 2832 and 1031, and a fingerprint spectrum with peaks at 808, 970, (1031), 1051, 1144 and 1179 cm-1. Anal. (C10H14OS) C,H.
A solution of 11.2 g 2-ethyl-4-(methylthio)anisole and 9 g dichloro-methyl methyl ether in 200 mL dry CH2Cl2 was treated with 13 g anhydrous aluminum chloride, added a bit at a time. The color progressed from pink to claret to deep claret, with a modest evolution of HCl. Stirring was continued for 1 h, then the reaction was quenched by the cautious addition of 250 mL H2O. The two phase mixture was stirred an additional hour and then separated. The aqueous phase was extracted with 2x100 mL CH2Cl2. The organics were pooled, washed with 5% NaOH, then with saturated brine, and the solvent removed under vacuum. The residue was an amber oil weighing 13.7 g. This was distilled at 0.2 mm/Hg. A first fraction was a yellow oil boiling at 90-100 °C, and weighing 2.9 g. It was a mixture of starting anisole and the desired benzaldehyde. A second fraction, boiling at 100-130 °C was a viscous yellow oil weighing 4.8 g. By TLC it was free of starting anisole, and contained a sizeable quantity of a second benzaldehyde. From this fraction, seed crystal was obtained, and when the oil was dissolved in an equal volume of MeOH, the seed took, producing a yellow solid. This was filtered and air dried, to give 2.2 g of 4-ethyl-5-methoxy-2-(methylthio)benzaldehyde with a mp of 62-63 °C. A small sample from MeOH was almost white, and melted at 61-62 °C. The mixed mp with 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde (57-58 °C) was severely depressed (37-44 °C). A cooled solution of the first fraction of the distillation, in MeOH, provided an additional 1.6 g product, with a mp 59-61 °C. The combined mother liquors gave additional product for an overall weight of 5.3 g. Anal. (C11H14O2S) C,H.
A solution of 1.9 g 4-ethyl-5-methoxy-2-(methylthio)benzaldehyde in 75 mL nitroethane was treated with 0.3 g anhydrous ammonium acetate, and held on the steam bath for 2.5 h. The excess solvent/reagent was removed under vacuum, and the deep orange oil residue was dissolved in 10 mL boiling MeOH. As this cooled, there was the spontaneous generation of crystals. After cooling in an ice bath for a few h, these were removed by filtration, washed with MeOH, and air dried to constant weight. A total of 1.4 g of 1-(4-ethyl-5-methoxy-2-methylthiophenyl)-2-nitropropene was obtained as canary-yellow crystals melting at 83-84 °C which was not improved by recrystallization from MeOH. Anal. (C13H17NO3S) C,H.
To a solution of 1.5 g LAH in 30 mL anhydrous THF that was cooled to 0 °C and stirred under a He atmosphere, there was added, slowly, 1.05 mL freshly prepared 100% H2SO4 (prepared by adding 0.9 g 20% fuming H2SO4 to 1.0 g 96% concentrated H2SO4). This was followed by the addition of a solution of 1.4 g 1-(4-ethyl-5-methoxy-2-methylthiophenyl)-2-nitropropene in 20 mL THF, over the course of 10 min. The color of the nitrostyrene solution was discharged immediately upon addition. With continued stirring, this was allowed to come to room temperature, and then to a gentle reflux for 2 h. After cooling again to room temperature, the excess hydride was destroyed by the addition of IPA. Sufficient 5% NaOH was added to generate the inorganic salts as a loose filterable mass, and these were removed by filtration. The filter cake was well washed with additional IPA, and the combined mother liquors and washes were stripped of solvent under vacuum. The residue was dissolved in 100 mL dilute H2SO4, washed with CH2Cl2, made basic with 5% NaOH, and extracted with 2x75 mL CH2Cl2. Removal of the solvent gave a residue that was distilled at 102-117 °C at 0.15 mm/Hg. The colorless liquid that distilled (0.7 g) was dissolved in 6 mL IPA and neutralized with 11 drops of concentrated HCl. The solids that formed were dissolved by heating the mixture briefly to a boil, and this clear solution was diluted with 20 mL anhydrous Et2O. The white crystals of 4-ethyl-5-methoxy-2-methylthioamphetamine hydrochloride (2-TOET) weighed 0.6 g and had a mp of 164-167 °C. Anal. (C13H22ClNOS) C,H.
DOSAGE: greater than 65 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 50 mg) After about an hour and a half, I found myself a little light-headed. And maybe a feeling of being physically a bit fragile. I ate something, but there was not much joy in eating. And the next day there was some residual fragility, whatever that means. Ahead with caution.
(with 65 mg) During the day this was barely noticeable, but pleasant.
EXTENSIONS AND COMMENTARY: It seems as if the sulfur in the 2-position makes things less interesting, and less potent, than when it is in the 5-position. 2-TOM required twice the dosage of 5-TOM, and here it appears that it could well take a dosage of twice that required for 5-TOET, to get 2-TOET off the ground. There is an understandable reluctance to push on upwards in dosage with a new and unknown compound, when there are feelings of physical discomfort that outweigh the mental effects. There is nothing tangible here. In the complete report of the 50 milligram trial, there is a mention of an inability to effect erection, and this with the light-headedness and disinterest in food, all suggest some involvement with the sympathetic nervous system. And with these subtle effects persisting into the next day, why push higher? Instinct said to leave it alone. So I left it alone.
The 2-carbon analogue, 2C-2-TOET, was made from the same aldehyde intermediate. The appropriate nitrostyrene came smoothly from the aldehyde and nitromethane, and gave glistening pumpkin-orange crystals from methanol, that melted at 93-94 °C. Anal. (C12H15NO3S) C,H. The final phenethylamine hydrochloride salt was prepared from its reduction with aluminum hydride in THF, and was isolated in the usual manner. It was a white crystalline mass that melted at 226-227 °C. It, as with the other 2-carbon analogues of the TOMs and TOETs, remains untasted as of the moment.
#170 5-TOET; 4-ETHYL-2-METHOXY-5-METHYLTHIOAMPHETAMINE
SYNTHESIS: A solution of 25 g 3-ethylphenol in 100 mL Et2O was equipped with a magnetic stirrer, and cooled to 0 °C with an external ice bath. There was added 16 mL DMSO. Then, a total of 15 mL chlorosulfonic acid was added dropwise, over the course of 30 min. The reaction was allowed to return to room temperature and stirred overnight. The overhead Et2O phase was removed by decantation, and the light-colored residue was dissolved in 100 mL IPA. The clear solution spontaneously generated white crystals which were allowed to stand for 1 h, removed by filtration, and lightly washed with IPA. After air-drying, this crop of dimethyl-(2-ethyl-4-hydroxyphenyl)-sulfonium chloride weighed 20.0 g and had a mp of 168-170 °C without obvious effervescence. A solution of 19.8 g of this sulfonium salt in 200 mL H2O was diluted with 500 mL MeOH, and there was added 30 g NaOH. This was heated to reflux on the steam bath. There was an initial deposition of some white solids, but after 36 h the solution was almost clear. The excess MeOH was removed under vacuum, and the non-volatiles were poured into 1 L H2O. This was acidified with HCl, and extracted with 3x100 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum. The residue, 12.6 g of an amber oil, was distilled at 95-120 °C at 0.3 mm/Hg to give 10.0 g of 3-ethyl-4-(methylthio)phenol as an off-white oil. This spontaneously crystallized to a solid that had a mp of 47-49 °C. Recrystallization of an analytical sample from cyclohexane gave a mp of 47-48 °C.
To a solution of 9.7 g 3-ethyl-4-(methylthio)phenol in 50 mL MeOH there was added a solution of 4.6 g 85% KOH in 50 mL hot MeOH. There was then added 5.4 mL methyl iodide and the mixture was held at reflux on the steam bath for 18 h. Removal of the solvent under vacuum gave a residue that was poured into 1 L H2O and made strongly basic by the addition of 5% NaOH. This was extracted with 3x75 mL CH2Cl2, and the extracts were pooled and the solvent removed under vacuum. There remained 11.0 g of an almost white oil with a startling apple smell. This oil was distilled at 78-88 °C at 0.3 mm/Hg to give 7.9 g 3-ethyl-4-(methylthio)anisole as a white oil. Anal. (C10H14OS) C,H.
A mixture of 7.8 g POCl3 and 6.9 g N-methylformanilide was heated on the steam bath for a few min, until there was the development of a deep claret color. This was added to 7.7 g 3-ethyl-4-(methylthio)anisole and the mixture was heated on the steam bath for 2 h. This was poured into 400 mL H2O and stirred overnight, which produced an oily phase with no signs of crystals. The entire reaction mixture was extracted with 3x75 mL CH2Cl2, and the pooled extracts washed with H2O. Removal of the solvent under vacuum gave 9.2 g of a residue. This was suspended in 25 mL hexane, and after 1 h standing, the overhead clear solution was decanted from the settled sludge. This hexane solution was stripped of solvent under vacuum, giving 7.7 g of an oil that by TLC was a mixture of starting ether and desired aldehyde. This was distilled at 0.25 mm/Hg to give three fractions, the first boiling at 75-100 °C (2.7 g) and the second at 100-115 °C (2.6 g). These were largely starting ether and aldehyde, and were chemically processed below. A third fraction, boiling at 120-140 °C, solidified in the receiver, weighed 1.6 g, and was largely the desired aldehyde. Cuts #1 and #2 (5.3 g of what was mostly recovered aldehyde) were resubmitted to the Vilsmeier reaction. A mixture of 5.4 g POCl3 and 4.7 g N-methylformanilide was heated on the steam bath until it became claret-colored. The recovered aldehyde was added, and the mixture was heated overnight on the steam bath. This was poured into 500 mL H2O. The heavy tar that was knocked out was extracted with 3x75 mL CH2Cl2, and the solvent was removed from the pooled extracts under vacuum. Some 5.8 g of residue was obtained, and this was heated to 120 °C at 0.2 mm/Hg to remove all materials lower boiling than the desired aldehyde. The very dark pot was extracted with 3x50 mL boiling hexane, and removal of the solvent from these pooled extracts under vacuum gave 0.9 g of a yellow oil. This was distilled at 0.2 mm/Hg to give a fraction boiling at 130-140 °C which spontaneously crystallized. This pressed on a porous plate gave almost white crystals with a mp of 55-57 °C. Recrystallization from 0.3 mL cyclohexane provided 0.3 g of 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde with a mp of 57-58 °C. The total yield was 1.9 g. Anal. (C11H14O2S) C,H.
To a solution of 1.2 g 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde in 25 mL nitroethane there was added 0.25 g anhydrous ammonium acetate and the mixture was heated on the steam bath. The initial color was green, but this quickly changed to the more usual yellow which darkened as the reaction mixture was heated. After 1.5 h heating, the excess solvent/reagent was removed in vacuo. The yellow residue was dissolved in 10 mL hot MeOH and allowed to stand in the refrigerator overnight. There was an orange oil layer formed underneath the MeOH. A small sample of this was scratched externally with dry ice, and seed was obtained. The orange oil layer slowly set to crystals which, after a few h, were removed by filtration to give 1.3 g of a slightly sticky orange solid with a mp of 43-45 °C. This was recrystallized from 8 mL boiling MeOH to give, after cooling, filtering, and air drying to constant weight, 1.1 g of 1-(4-ethyl-2-methoxy-5-methylthiophenyl)-2-nitropropene as electrostatic yellow crystals melting at 59-60 °C. Anal. (C13H17NO3S) C,H.
A solution of 1.0 g LAH in 25 mL tetrahydrofuran was cooled, under He, to 0 °C with an external ice bath. With good stirring there was added 0.6 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 1.1 g of 1-(4-ethyl-2-methoxy-5-methylthio)-2-nitropropene in a small amount of THF. After 10 min further stirring, it was brought up to room temperature and allowed to stand for several days. The excess hydride was destroyed by the cautious addition of IPA followed by sufficient 15% NaOH to give a white granular character to the aluminum oxide, and to assure that the reaction mixture was basic. This was filtered, and the filter cake washed first with THF and then with IPA. The filtrate and washings were pooled and stripped of solvent under vacuum providing a pale amber residue. This was dissolved in 50 mL of dilute H2SO4 and washed with 2x50 mL CH2Cl2. The aqueous phase was made basic with 5% NaOH, and extracted wit 2x50 mL CH2Cl2. These extracts were pooled, stripped under vacuum, and distilled at 0.15 mm/Hg. The fraction with a bp of 102-128 °C weighed 0.4 g and was a colorless liquid. This was dissolved in a small amount of IPA, neutralized with concentrated HCl and diluted with anhydrous Et2O to provide the 4-ethyl-2-methoxy-5-methylthioamphetamine hydrochloride (5-TOET) which weighed 0.6 g and melted at 146-147 °C. Anal. (C13H22ClNOS) C,H.
DOSAGE: 12 - 25 mg.
DURATION: 8 - 24 h.
QUALITATIVE COMMENTS: (with 8 mg) After my totally freaky experience on the very closely related compound in this series, 5-TOM, I intended to approach this with some caution. Three milligrams was without effects, so I tried eight milligrams. I was a little light-headed, and saw sort of a brightness around trees against the blue sky. Noticed movement on couch in living room, and there was some activity in the curtains, almost 2C-B like. In the evening writing was still difficult, and there was eye dilation but minimal nystagmus. My sleep was fitful, but certainly there was no hint of the 5-TOM storm.
(with 18 mg) This was too much. There was an exhausting visual hallucinatory tinsel, continuous movement, and there was no escape. It popped into an LSD-like thing, strong, restless, constantly changing, with too much input. I had to take a Miltown to calm down enough for an attempt at sleep. In the morning, a day later, I was still 1.5 + and tired of it. It was the next day after that before I was completely clear.
(with 20 mg) This has the makings of a superb, extraordinary material. I didn't get to a full plus two, maybe something around a plus one and three quarters. The eyes-closed fantasy was exceptional, with new dimensions. The nature of the fantasy, the feeling that one had about the fantasy figures and landscapes, was the essence of joy, beauty, lovingness, serenity. A glimpse of what true heaven is supposed to feel like. Or maybe a button in the brain was pushed which has not been pushed by previous chemicals. Insight? Don't know yet. I was able to function without difficulty with eyes closed or open. Erotic absolutely exquisite. In fact, the entire experience was exquisite. Next day, same sense of serene, quiet joy/beauty persisted for most of the day. A true healing potential. Onwards and upwards. This one could be extraordinary.
(with 30 mg) Tried to focus on cosmic questions, and succeeded. Very little fantasy images for the first 2-3 hours. After that, lovely interacting, music okay but not vital. On this compound the Brahms Concerto #1 gave vivid 'memory' impressions of house and vegetable garden, like a primitive painting. Tremendous nostalgia for a place I've never seen.
EXTENSIONS AND COMMENTARY: With the extraordinary experience that had been observed with one person with 5-TOM, this ethyl homologue was not only run up with special caution, but that individual ran his own personal titration. And he proved to be perhaps twice as sensitive to 5-TOET than any of the other subjects. An approach to what might just be some unusual metabolic idiosyncrasy on the part of his liver, is discussed in the recipe for TOMSO.
The initials of TOET progressed quite logically from TOM, in an exact parallel with the relationship between the corresponding sulfur-free analogues, where the ethyl compound is DOET and the methyl counterpart is DOM. RTS for "thio" which is the chemical nomenclature term for the replacement of an oxygen atom with a sulfur atom. And, as has been discussed in the text of this volume, the peculiarities of pronunciation in this series are interesting, to say the least. TOM is no problem. But TOET could have any of several pronunciations such as "Two-it", or "Tow-it", or "Too-wet", but somehow the one syllable term "Twat" became regularly used, and the family was generally referred to as the RToms and "wats." The almost-obscene meaning of the latter was progressively forgotten with usage, and has led to some raised eyebrows at occasional seminars when these compounds are discussed. And not only at seminars. Once at the between-acts intermission at the Berkeley Repertory Theater, the topic came up and the phrase was used. There was a stunned silence about us within the circle of hearing, and we seemed to have been given a little extra room immediately thereafter.
As with the other members of the TOM's and TOET's, the phenethylamine homologue of 5-TOET was synthesized, but had never been started in human evaluation. The aldehyde from above, 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde, was condensed with nitroethane (as reagent and as solvent) and with ammonium acetate as catalyst to give the nitrostyrene as spectacular canary-yellow electrostatic crystals with a mp of 91-92 °C. Anal. (C12H15NO3S) C,H. This was reduced with aluminum hydride (from cold THF-dissolved lithium aluminum hydride and 100% sulfuric acid) to the phenethylamine 4-ethyl-2-methoxy-5-methylthiophenethylamine (2C-5-TOET) which, when totally freed from water of hydration by drying at 100 °C under a hard vacuum, had a mp of 216-217 °C. Anal. (C12H20ClNOS) C,H.
#171 2-TOM; 5-METHOXY-4-METHYL-2-METHYLTHIOAMPHETAMINE
SYNTHESIS: To a solution of 64.8 g of o-cresol and 56 g dimethyl sulfoxide in 300 mL Et2O, cooled with an external ice bath with vigorous stirring, there was added 40 mL chlorosulfonic acid dropwise over the course of 30 min. The cooling bath was removed, and the two phase mixture was mechanically stirred at room temperature for 12 h. The Et2O phase was then discarded, and the deep red residue that remained was thoroughly triturated under 300 mL IPA, producing a suspension of pale pink solids. These were removed by filtration, washed with an additional 150 mL IPA, and allowed to air dry. The yield of dimethyl (4-hydroxy-3-methylphenyl)sulfonium chloride was 31.6 g and, upon recrystallization from aqueous acetone, had a mp of 155-156 °C, with effervescence. Anal. (C9H13ClOS) C,H,S. This analysis established the anion of this salt as the chloride, whereas the literature had claimed, without evidence, that it was the bisulfate. The thermal pyrolysis of 31.0 g of dimethyl (4-hydroxy-3-methylphenyl)sulfonium chloride resulted first in the formation of a melt, followed by the vigorous evolution of methyl chloride. The open flame was maintained on the flask until there was no more gas evolution. This was then cooled, dissolved in 200 mL CH2Cl2, and extracted with 3x100 mL of 5% NaOH. The aqueous extracts were pooled, acidified with concentrated HCl, and extracted with 3x75 mL CH2Cl2. The solvent was removed under vacuum, and the residue distilled at 100-110 °C at 0.5 mm/Hg yielding 22.0 g of 2-methyl-4-(methylthio)phenol as a white crystalline solid with a mp 36-37 °C.
To a solution of 25.5 g 2-methyl-4-(methylthio)phenol in 100 mL MeOH there was added a solution of 12 g 85% KOH in 60 mL hot MeOH, followed by the addition of 12.4 mL methyl iodide. The mixture was held at reflux for 16 h. The solvent was removed under vacuum, and the residue added to 400 mL H2O. This was made basic with 25% NaOH and extracted with 3x100 mL CH2Cl2. The extracts were pooled, the solvent removed under vacuum giving 28.3 g of a light, amber oil as residue. This was distilled at 72-80 °C at 0.5 mm/Hg to provide 2-methyl-4-(methylthio)anisole as a pale yellow oil. Anal. (C9H12OS) C,H. The same product can be made with the sulfonyl chloride and the thiol as intermediates. To 36.6 g 2-methylanisole there was added, with continuous stirring, a total of 38 mL chlorosulfonic acid at a modest rate. The exothermic reaction went through a complete spectrum of colors ending up, when the evolution of HCl had finally ceased, as deep amber. When it had returned again to room temperature, the reaction mixture was poured over a liter of cracked ice which, on mechanical stirring, produced a mass of white crystals. These were removed by filtration, washed with H2O, and sucked as dry as possible. The wet weight yield was over 40 g and the mp was about 49 °C. Recrystallization of an analytical sample of 4-methoxy-3-methylbenzenesulfonyl chloride from cyclohexane gave white crystals with a mp of 51-52 °C. A small sample of this acid chloride brought into reaction with ammonium hydroxide produced the sulfonamide which, after recrystallization from EtOAc, melted at 135-136 °C. To a slurry of 300 mL cracked ice and 75 mL concentrated H2SO4 in a round-bottomed flask equipped with a reflux condenser, there was added 43 g of the slightly wet 4-methoxy-3-methylbenzenesulfonyl chloride followed by 75 g elemental zinc dust. The temperature was raised to a reflux which was maintained for 2 h. The reaction mixture was cooled and filtered, with the finely ground filter cake being washed alternately with H2O and with CH2Cl2. The combined mother liquor and washings were diluted with 1 L H2O, the phases separated, and the aqueous phase extracted with 100 mL CH2Cl2 which was added to the organic phase. This was washed with 100 mL H2O, and the solvent removed under vacuum. The residue was a pale amber oil weighing 27.3 g and it slowly set up to a crystalline mass that smelled of banana oil. A portion of this, pressed on a porous plate, gave a waxy solid with a mp of 39-43 °C which, on recrystallization from MeOH, gave 4-methoxy-3-(methyl)thiophenol with a mp of 45-46 °C. Anal. (C8H10OS) C,H. A solution of 24 g of the crude thiol in 100 mL MeOH was treated with a solution of 17 g KOH 85% pellets in 100 mL hot MeOH, and to this there was added 16 mL of methyl iodide. This was held at reflux on the steam bath for 1.5 h, then stripped of solvent under vacuum, added to 1 L H2O, and made strongly basic with 25% NaOH. Extraction with 3x100 mL CH2Cl2, pooling of the extracts, and removal of the solvent, gave an amber oil weighing 22.6 g. This was distilled at 70-80 °C at 0.7 mm/Hg to give 16.3 g of 2-methyl-4-(methylthio)anisole as a white oil, identical in all respects to the product that came from the sulfonium salt pyrolysis above.
A solution of 22.1 g 2-methyl-4-(methylthio)anisole and 17.5 g dichloromethyl methyl ether in 600 mL CH2Cl2 was vigorously stirred, and treated with 24.5 g anhydrous aluminum chloride added portion-wise over the course of 1 min. Stirring was continued for 20 min while the color developed to a dark red. There was added 500 mL H2O with caution, and stirring was continued until the initial yellow solids redissolved and there were two distinct phases formed. These were separated, and the aqueous phase was extracted with 3x100 mL CH2Cl2. The original organic phase and the pooled extracts were combined and washed with 5% NaOH. The organic solvent was removed under vacuum. The residue was distilled, giving two major fractions. A forerun (85-95 °C at 0.5 mm/Hg) proved to be largely starting ether. The major fraction (8.4 g, boiling at 95-120 °C) consisted of two materials, both benzaldehydes. Crystallization of this fraction from 30 mL cyclohexane provided, after filtering, washing and air drying, 2.9 g of 5-methoxy-4-methyl-2-(methylthio)benzaldehyde as a pale yellow crystalline solid with a mp of 69-70 °C. Anal. (C10H12O2S) C,H. The mother liquor from this crystallization contained a slower-moving component, 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 TOET's, 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 wasn't 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 didn't understand. In retrospect, I suspect the horizontal lines were only expressions of how my mind was reacting to the material. I don't 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 wasn't 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 didn't 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 wasn't 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.
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 day's 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 "to tomso" 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 "inactive" 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 couldn't 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
The need for the next alternative route application is connected with
the poor yield of nitrostyrene on nitromethane condensation stage
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
