Pihkal

by Alexander Shulgin

  (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 didnUt 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? DonUt 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 IUve 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 RthioS 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 RTwo-itS, or RTow-itS, or RToo-wetS, but somehow the one syllable term RTwatS became regularly used, and the family was generally referred to as the RToms and Twats.S 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 TOETUs, 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,