Pihkal

by Alexander Shulgin

  A solution of 10 g 2-mercapto-4-methoxyphenol in 100 mL MEK was added over the course of 1 h to a vigorously stirred suspension of 25 g finely powdered anhydrous K2CO3 in 200 mL MEK that contained 14 g methylene bromide. The reflux was maintained for 48 h. After cooling, the mixture was freed of solids by filtration and the filter cake washed with 50 mL additional MEK. The combined washes and filtrate were stripped of solvent under vacuum, and the product distilled to give 3.3 g of 5-methoxy-1,3-benzoxathiol as a yellowing oil that had a bp of 110-120 !C at 1.7 mm/Hg. There was considerable residue in the pot, which was discarded. The NMR spectrum was excellent, with the methylene protons a two-hydrogen singlet at 5.6

  ppm.

  To a mixture of 3.2 g POCl3 and 2.8 g N-methylformanilide that had been heated briefly on the steam bath (to the formation of a deep claret color) there was added 2.3 g 5-methoxy-1,3-benzoxathiol, and steam bath heating was continued for an additional 5 min. The reaction mixture was poured into 100 mL H2O, and after a few minutes stirring, the insolubles changed to a loose solid. This was collected by filtration, H2O washed and, after sucking as dry as possible, recrystallized from 30 mL boiling MeOH. This provided 1.9 g of 6-formyl-5-methoxy-1,3-benzoxathiol as brownish needles that melted at 119-120 !C.

  A solution of 1.5 g 6-formyl-5-methoxy-1,3-benzoxathiol in 50 mL

  nitroethane was treated with 0.3 g anhydrous ammonium acetate and heated on the steam bath for 5 h. Removal of the solvent under vacuum gave a residue that crystallized. This was recrystallized from 110 mL

  boiling EtOH providing, after fil-tering and air drying, 1.3 g 5-methoxy-6-(2-nitro-1-propenyl)-1,3-benzoxathiol as San Francisco Giants-orange-colored crystals.

  A solution of AH was prepared by the treatment of a solution of 1.3 g LAH in 10 mL THF, at 0 !C and under He, with 0.8 mL 100% H2SO4. A solution of 1.1 g of 5-methoxy-6-(2-nitro-1-propenyl)-1,3-benzoxathiol in 25 mL THF was added dropwise, and the stirring was continued for 1

  h. After a brief period at reflux, the reaction mixture was returned to room temperature, and the excess hydride destroyed by the addition of IPA. The salts were converted to a filterable mass by the addition of 5% NaOH and, after filtering and washing with IPA, the combined filtrate and washings were stripped of solvent under vacuum. The residue was dissolved in dilute H2SO4 which was washed with 3x75 mL

  CH2Cl2 and then, after being made basic with 25% NaOH, the product was extracted with 2x75 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum. Distillation of the residue gave a fraction that boiled at 140-155 !C at 0.3 mm/Hg which weighed 0.7 g.

  This was dissolved in 4 mL IPA, neutralized with 14 drops of concentrated HCl, heated to effect complete solution, then diluted with 10 mL of anhydrous Et2O. The white crystals that formed were removed, Et2O washed, and air dried to give 0.6 g 6-(2-aminopropyl)-5-methoxy-1,3-benzoxathiol hydrochloride (4T-MMDA-2).

  DOSAGE: greater than 25 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 25 mg) At three hours after having taken the material, I felt that there might have been a little exhilaration.

  And maybe a hint of tremor and of teeth clench. Perhaps this is a threshold dose.

  EXTENSIONS AND COMMENTARY: There is no logical way to try to guess where the active level of this might be. In a comparison of 4-oxy with 4-thio- and with 4-alkyl (as, for example, TMA-2, PARA-DOT and DOM) the analogue with the sulfur atom lies intermediate in potency between the oxygen atom and the carbon atom. Then, perhaps, 4T-MMDA-2

  should be somewhat more potent than MMDA-2. Which is where the trials have gone to, and the absence of effects therefore declares that line of reasoning invalid. What else could be used for clues? The whole benzofuran project, which had the same cyclic nature, was without activity. They had a carbon where the sulfur was of 4T-MMDA- 2, so, by that reckoning, this compound should be even less active. Maybe that is the formula to follow. The bottom line is inescapable. None of these extrapolations can hold a candle to the only experiment that can give believable findings, the actual trial of a new compound in man.

  The positional isomer of the heterocyclic carbonate used here is also known. Instead of using benzoquinone as a starting material with thiourea as the sulfur source (giving the 1,4- oxygen orientation), one can start with resorcinol in reaction with ammonium thiocyanate as the sulfur source (in the presence of copper sulfate) and get the positional isomer with a 1,3- oxygen orientation. This material (also known as thioxolone, or tioxolone, or 6-hydroxy-1,3-benzoxathiol-2-one, and which is commercially available) should follow the same chemistry shown here for the 5-hydroxy analogue, and give 5T-MMDA-2

  (5-(2-aminopropyl)-6-methoxy-1,3-benzoxathiole or 2-methoxy-5,4-methylenethiooxyamphetamine) as a final product. I would guess, based on the findings that compare 5-TOM with DOM, that this would be a relatively low-potency compound. At least it should be an easy one to make!

  168 TMPEA; 2,4,5-TRIMETHOXYPHENETHYLAMINE

  SYNTHESIS: To a solution of 39.2 g 2,4,5-trimethoxybenzaldehyde in 160

  mL nitromethane there was added 7.0 g anhydrous ammonium acetate, and the mixture was heated on the steam bath for 2 h. The excesssolvent/reagent was removed under vacuum, leaving a deeply colored residue that spontaneously crystallized. This was mechanically removed and triturated under 60 mL cold MeOH.

  Filtration, washing with cold MeOH and air drying, gave 49.3 g of bright orange crystals. Trial recrystallizations from EtOAc gave a mp of 132-133 !C; from CH3CN, 130.5-131.5 !C. The entire product was recrystallized from 1.1 L boiling IPA to provide, after filtration, IPA washing, and air drying, 34.5 g of '-nitro-2,4,5-trimethoxystyrene as yum-yum orange crystals with a mp of 132-133 !C. Literature values are usual one-degree ranges, anywhere in the area of 127-130 !C.

  To a suspension of 30 g powdered LAH in 800 mL of well stirred and refluxing anhydrous THF there was added a solution of 34.9 g '-nitro-2,4,5-trimethoxystyrene in 200 mL anhydrous THF. The mixture was maintained at reflux for an additional 36 h, cooled, and the excess hydride activity destroyed by the addition of 30 mL H2O

  followed by 30 mL 15% NaOH, and finally with another 90 mL H2O. The solids were removed by filtration, washed with THF, and the pooled mother liquor and washings stripped of solvent under vacuum. The residue was dissolved in CH2Cl2, washed with both 5% NaOH and then H2O, removing much of the color. It was then extracted with 3x75 mL N

  HCl. The pooled red-colored acid extracts were washed with CH2Cl2, made basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2. Removal of the solvent gave some 25 g of residue which was dissolved in 100 mL

  IPA and neutralized with concentrated HCl. The crystalline mass that formed was diluted with an equal volume of Et2O, and the solids removed by filtration. Washing with cold IPA, followed by Et2O and air drying, gave 17.7 g of 2,4,5-trimethoxyphenethylamine hydrochloride (TMPEA) as a white product. The reported melting point was 187-188 !C.

  DOSAGE: greater than 300 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with less than 300 mg) Since it was not easy, however, to judge the extent of a 'Rausch'-action from experiments on animals, some injections of beta-2,4,5-trimethoxyphenethylamine were administered to the author, and finally a control test was carried out with an equal quantity of mescaline. The action of both these substances in these experiments agreed only to a limited extent with the effects described for mescaline by, for example, Beringer. It must be remembered, however, in this connection, that the quantities used by Beringer were larger than the doses administered in these experiments. Nevertheless, it may be concluded that the pharmacological action of beta-2,4,5-trimethoxyphenethylamine agrees to a large extent with that of mescaline. However, the new compound had more unpleasant secondary effects (nausea) and did not bring about the euphoristic state caused by mescaline.

  (with 300 mg) Under double blind conditions, I was unable to distinguish this from a placebo. Both were without any of the changes described after the ingestion of psychotomimetic drugs.


  (with 200 mg, followed after 45 minutes, with 100 mg mescaline) RThe normally modest effects known to be due to mescaline alone at this level, were strongly potentiated with the earlier taking of 2,4,5-TMPEA. The effects were stronger as well as longer lived.

  EXTENSIONS AND COMMENTARY: The code letters used for this drug are not as ambiguous as they might seem at first glance. A large number of the 2-carbon homologues are given names based on the code for the 3-carbon compound. On that basis, this should be 2C-TMA-2, since it is the 2-carbon counterpart of TMA-2. But since the first of the trimethoxyphenethylamines already had a trivial name, mescaline, the code TMPEA was unassigned. So, here is the logical place to use it.

  There have been just two reports published of self-experimentation with TMPEA, and these comments are taken from them.

  The first is presented here, word for word, as it was originally published (this was in 1931). It leaves much to be desired. The administration was by injection (intramuscular injection?). The dose was not given, but it was less than those reported by Beringer in his studies with mescaline, and this latter experimenter's published levels were all between 300 and 500 milligrams. What can one conclude from all this? Only that TMPEA apparently did not measure up to mescaline in his comparisons.

  The second, reported some 40 years later, is not really contradictory.

  Here the TMPEA was administered orally, and the subject surrounded himself with a battery of psychological tests. This might allow statistics to provide an aura of validity to the observations. But the comments are pretty self-explanatory. The drug was not active in its own right, but when employed preliminary to mescaline, greatly enhanced the effects of the latter.

  This is an area of research that deserves more attention. The simple compound that results from the stripping of all three of the O-methyl groups from TMPEA is the extremely potent neurotoxin, 6-hydroxydopamine. When it is ad-ministered to an otherwise intact experimental animal, it produces sympathectomy, effectively destroying the sympathetic nervous system. And some of the methyl groups of TMPEA are known to be stripped off through the normal metabolic processes that occur in the liver. There are many fascinating psychedelics that have a signature of methoxyl groups para to one-another. It is known that they, too, can lose a methyl group or two. It would be intriguing to see if there was some biochemical overlap between the metabolism of some of these centrally active drugs and the metabolic fate of 6-hydroxydopamine. But in a test animal, of course, rather than in man.

  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.