Pihkal

by Alexander Shulgin

  To this crude 1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-iodoethane there was added a solution of 3.7 g potassium phthalimide in 50 mL

  anhydrous DMF, and all was heated on the steam bath. The reaction seemed to be complete after 15 min (as seen by TLC) and the addition of a second batch of potassium phthalimide in DMF produced no further change. After adding to 500 mL of dilute NaOH, the aqueous phase was extracted with 2x75 mL Et2O. These extracts were combined, washed first with dilute NaOH and then with dilute H2SO4, dried over anhydrous K2CO3, and the solvent removed under vacuum which provided an amber oil as residue. This was triturated under cold MeOH giving white solids which were recrystallized from 20 mL MeOH. Thus there was obtained 0.9 g of

  1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-phthalimidoethane as white crystals that melted at 79-80.5 !C. A small sample was recrystallized from EtOH to give large flat needles with a mp of 81-82 !C. Anal.

  (C21H23NO4S) C,H.

  A suspension of 0.8 g of the crystallized 1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-phthalimidoethane in 25 mL

  of n-butanol was treated with 2 mL of 66% hydrazine, and the mixture was heated on the steam bath for 0.5 h. Initially all went into solution, and then there was the separation of solids that resembled cottage cheese. The reaction mixture was added to 150 mL dilute H2SO4. The solids were removed by filtration, and the filtrate was washed with 3x50 mL CH2Cl2. These washes were discarded. The H2O

  phase was then made basic with aqueous NaOH, extracted with 2x75 mL

  CH2Cl2, and the solvent from these pooled extracts removed under vacuum. The residue was distilled at 135-155 !C at 0.3 mm/Hg to give 0.45 g of a colorless oil. This was dissolved in 2.5 mL IPA, neutralized with 5 drops of concentrated HCl, and diluted with 10 mL

  anhydrous Et2O. The solution became cloudy, and then deposited lustrous white plates. These were removed by filtration, washed with additional Et2O, and air dried to give 0.4 g of 3-ethoxy-5-ethylthio-4-methoxyphenethylamine hydrochloride (3-TSB) with a mp of 153.5-154.5 !C. Anal. (C13H22ClNO2S) C,H.

  DOSAGE: greater than 200 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 200 mg) No effects whatsoever, neither mental nor physical.

  EXTENSIONS AND COMMENTARY: The elephant labored and brought forth a mouse. A lot of work for a material without activity.

  I have used the term RscrudgeS in this and other recipes, without defining it. With this aldehyde, as with most aldehydes in this nitrostyrene synthesis reaction where there is no ortho-substituent on the benzaldehyde, the reaction progress should be carefully followed by thin-layer chromatography. As the aldehyde disappears from the reaction mixture, the nitrostyrene appears, but there is usually the development of one or more slower moving components as seen by TLC.

  Such a wrong-product is called scrudge. The reaction should be continuously titrated, and stopped when there is a favorable balance between the aldehyde being mostly gone, the nitrostyrene being mostly made, and the slower-moving scrudge components being not yet too plentiful. Methylene chloride is an excellent solvent to try first, with silica gel plates and UV detection. The nitrostyrene is always the fastest moving component of the reaction mixture and often fluoresces a dull purple. The starting aldehyde is the second spot and usually fluoresces white or pale yellow. The scrudge spots then occur in a cascade from the aldehyde to the origin. A maddening property is that they are yellow or brown colored, and in the probe mass spectrograph they can crack to give rise to what appears to be the right nitrostyrene. Usually, they are high melting.

  In this preparation, there was not one but several scrudges, and little if any nitrostyrene. The same was true for the other of the diethyl compounds such as 3-TASB, 5-TASB and 3-T-TRIS. Thus, it is preferable to circumvent this usual synthetic step by using the Wittig reaction instead, as described here.

  177 4-TSB; 4-THIOSYMBESCALINE;

  3,5-DIETHOXY-4-METHYLTHIOPHENETHYLAMINE

  SYNTHESIS: A solution of 12.1 g N,N,NU,NU-tetramethylethylenediamine and 16.6 g of 1,3-diethoxybenzene was made in 200 mL 30-60 !C

  petroleum ether. This was stirred vigorously under a N2 atmosphere and cooled to 0 !C with an external ice bath. There was added 66 mL

  of 1.6 M butyllithium in hexane. The stirred reaction mixture became a little cloudy and then gradually formed a white granular precipitate. This was brought to room temperature, stirred for 0.5 h, and returned again to 0 !C. There was added 9.45 g of dimethyl disulfide which converted the loose precipitate to a creamy texture.

  The reaction was exothermic. After being held 0.5 h at reflux temperature, the reaction mixture was added to 600 mL dilute H2SO4.

  There was the immediate formation of white solids which were insoluble in either phase. The petroleum ether phase was separated, and the aqueous phase extracted with 3x100 mL Et2O. The organics were combined, and the solvents removed under vacuum. There was obtained as residue 24.8 g of a slightly oily crystalline solid that, after trituration under 30 mL cold hexane, filtering, and air drying, weighed 16.9 g. This product, 2,6-diethoxythioanisole, had a mp of 71-72 !C which was not im-proved by recrystallization from methylcyclopentane. Anal. (C11H16O2S) C,H.

  To a stirred solution of 16.7 g of 2,6-diethoxythioanisole in 175 mL

  CH2Cl2 there was added 13 g elemental bromine dissolved in 100 mL

  CH2Cl2. After stirring at ambient temperature 1 h, the dark solution was added to 150 mL H2O containing 1 g of sodium dithionite. Shaking immediately discharged the residual bromine color, and the organic phase was separated. The aqueous phase was extracted once with 100 mL

  CH2Cl2, the pooled extracts washed first with H2O, and then with saturated brine. Removal of the solvent under vacuum provided 28.6 g of a pale yellow oil with several globs of H2O present. This wet product was distilled at 118-125 !C at 0.25 mm/Hg to yield 3-bromo-2,6-diethoxythioanisole as a white oil weighing 21.5 g. It could not be crystallized. Anal. (C11H15BrO2S) C,H.

  To a solution of 19.3 g diisopropylamine in 75 mL hexane under a He atmosphere there was added 100 mL of 1.6 M butyllithium. The viscous mixture was loosened by the addition of 200 mL anhydrous THF, and this stirred mixture was cooled with an external ice bath. There was then added 4.0 mL of dry CH3CN, and 11.6 g of 3-bromo-2,6-diethoxythioanisole (which had been diluted with a little anhydrous THF). The deep red brown reaction mixture was stirred for 0.5 h, and then poured into 1 L dilute H2SO4. This was extracted with 3x75 mL CH2Cl2, the extracts pooled, washed with H2O, dried with anhydrous K2CO3, and the solvent was removed under vacuum. The residue was distilled at 0.3 mm/Hg yielding two fractions. The first fraction boiled at 120-140 !C and weighed 1.2 g. This fraction partially crystallized, but was not investigated further. The second fraction was 3,5-diethoxy-4-methylthiophenylacetonitrile, which came over at 135-160 !C, was a yellow liquid, weighed 3.2 g, but did not crystallize.

  A solution of LAH in anhydrous THF (30 mL of a 1.0 M solution) under N2 was cooled to 0 !C and vigorously stirred. There was added, dropwise, 0.78 mL 100% H2SO4, followed by 3.0 g 3,5-diethoxy-4-methylthiophenylacetonitrile diluted with a little anhydrous THF. The reaction mixture was stirred at 0 !C for a few min, then brought to reflux on the steam bath for 1.5 h. 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 with the conversion of aluminum oxide to a loose, white, filterable consistency. This was removed by filtration, and washed first with THF followed by 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 25% NaOH, and extracted with 3x100 mL CH2Cl2. After combining, the solvent was removed under vacuum providing an orange oil. This was distilled at 135-160 !C at 0.4 mm/Hg to give a light yellow oil. This was dissolved in 20 mL of IPA, and neutralized with 32 drops of concentrated HCl producing white crystals spontaneously. These were dissolved by bringing the IPA suspension to a boil on the steam bath and, with stirring, diluted with 80 mL of
warm anhydrous Et2O. There was the immediate formation of crystals which were removed by filtration, washed with an IPA/Et2O

  mixture, and then with Et2O. After air drying there was obtained 1.5

  g of 3,5-diethoxy-4-methylthiophenethylamine hydrochloride (4-TSB) as white crystals. The mp was 194.5-196 !C. Anal. (C13H22ClNO2S) C,H.

  DOSAGE: greater than 240 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 80 mg) There was a real effect about three hours into this experiment Q a little bit spacey while I was talking to Mr. X. But the talk went well, and we were all really friendly. There was no hint that he suspected anything. A couple of hours later, nothing.

  (with 160 mg) Twinges at a couple of hours, but the rest of the day disappointing as to any effect from the drug.

  (with 240 mg) No effects at all.

  EXTENSIONS AND COMMENTARY: Here is an excellent presentation of a report that shows false positives or maybe false negatives. Something at low levels. Nothing at higher levels. Always tend to trust the absence of an effect in preference to the presence of an effect, if one of the two observations is presumed to be in error.

  178 3-T-TRIS; 3-THIOTRESCALINE; 3-THIOTRISESCALINE; 3,4-DIETHOXY-5-ETHYLTHIOPHENETHYLAMINE

  SYNTHESIS: A solution of 11.5 g

  3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine (see under ASB 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 light formation of fine crystals. There was then added 25 mL of 1.6 N butyllithium in hexane and the mixture stirred for 15 min. This was followed by the addition of 5.8 g diethyl disulfide over the course of 20 min during which time the solution became increasingly cloudy with the eventual deposition of an insoluble gummy phase. The mixture was allowed to come to room temperature over the course of 1 h, and then added to 400 mL of dilute HCl. The organic phase was separated and stripped of solvent under vacuum. This residue was combined with the original aqueous phase, and the mixture was heated on the steam bath for 2 h. The aqueous mixture was cooled to room temperature, extracted with 3x100 mL

  CH2Cl2, the extracts pooled, washed with H2O, and the solvent removed under vacuum to yield 11.0 g of an amber oil. This was distilled at 130-150 !C at 0.2 mm/Hg to yield 7.2 g of 3,4-diethoxy-5-(ethylthio)benzaldehyde as a white oil that spontaneously crystallized. The crude product had a mp of 52-57 !C

  that increased to 57-58 !C upon recrystallization from EtOH. Anal.

  (C13H18O3S) C,H.

  A solution of 14.9 g methyltriphenylphosphonium bromide in 200 mL

  anhydrous THF was placed under a He atmosphere, well stirred, and cooled to 0 !C with an external ice water bath. There was then added 27.6 mL of 1.6 N butyllithium in hexane which resulted in the generation of a yellow color which was at first transient, and then stable. The reaction mixture was brought up to room temperature, and 6.8 g 3,4-diethoxy-5-(ethylthio)benzaldehyde in 50 mL THF was added dropwise dispelling the color, and the mixture was held at reflux on the steam bath for 1 h. The reaction was quenched in 800 mL H2O, the top layer separated, and the aqueous phase extracted with 2x75 mL of petroleum ether. The organic fractions were combined and the solvents removed under vacuum to give 12.0 g of the crude 3,4-diethoxy-5-ethylthiostyrene as a deep yellow oil.

  A solution of 5.6 g of borane-methyl sulfide complex (10 M BH3 in methyl sulfide) in 45 mL THF was placed in a He atmosphere, cooled to 0 !C, treated with 11.6 g of 2-methylbutene, and stirred for 1 h while returning to room temperature. To this there was added the crude 3,4-diethoxy-5-ethylthiostyrene in 25 mL THF and the stirring was continued for 1 h. The excess borane was destroyed with about 2 mL

  MeOH. There was then added 11.4 g elemental iodine followed by a solution of 2.2 g NaOH in 40 mL hot MeOH. This was followed by sufficient 25% NaOH to minimize the residual iodine color (about 4 mL

  was required). The reaction mixture was added to 500 mL H2O

  containing 4 g sodium hydrosulfite. This was extracted with 3x75 mL

  petroleum ether, and the pooled extracts stripped of solvent under vacuum to yield 24.5 g of crude

  1-(3,4-diethoxy-5-ethylthiophenyl)-2-iodoethane as a viscous yellow oil.

  This crude 1-(3,4-diethoxy-5-ethylthiophenyl)-2-iodoethane was added to a solution of 11.1 g potassium phthalimide in 80 mL DMF, and all was heated on the steam bath for 1.5 h. It was then flooded with 600

  mL H2O, made basic with NaOH, and extracted with 3x100 mL Et2O.

  Removal of the solvent under vacuum provided 18.5 g of a residue that was dried to a constant weight by heating under vacuum (0.2 mm/Hg).

  The solid residue was ground under MeOH, and then recrystallized from MeOH providing 1-(3,4-diethoxy-5-ethylthiophenyl)-2-phthalimidoethane as white granular crystals, with a mp of 86.5-87.5 !C. Anal.

  (C22H25NO4S) C,H.

  The recrystallized

  1-(3,4-diethoxy-5-ethylthiophenyl)-2-phthalimidoethane was dissolved in n-butanol, treated with 66% hydrazine, and the mixture heated on the steam bath for 1.5 h. This was then added to dilute H2SO4, the butanol separated, the aqueous phase washed with 2x75 mL Et2O. After being made basic with aqueous NaOH, the aqueous phase was extracted with 3x75 mL CH2Cl2 and the solvent removed under vacuum to provide a pale amber oil. This was distilled at 140-155 !C at 0.25 mm/Hg to give about 1 g of a white oil. The distillate was dissolved in 5 mL

  IPA, neutralized with concentrated HCl, and treated with 10 mL

  anhydrous Et2O to give a solution from which a white crystalline product slowly separated. These crystals, 3,4-diethoxy-5-ethylthiophenethylamine hydrochloride (3-T-TRIS) weighed 1.1 g and had a mp of 161-162 !C. Anal. (C14H24ClNO2S) C,H.

  DOSAGE: greater than 160 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 160 mg) There were no effects. At the 9th or 10th hour after having taken the material I was aware of some neurological irritability. I will not try this at any higher dosage, and let me stretch things a bit by a few percent in good conscience and say that this is less active than mescaline. This would allow it to be reported as < 1 M.U.

  EXTENSIONS AND COMMENTARY: The term RM.U.S pops up here and there in a lot of the earlier literature on these phenethylamines. It stands for Rmescaline unitsS and was used to give a quantitative measure for the relative potency of a compound. Since it became obvious quite early in these studies that mescaline, although the prototypic compound, was probably going to remain the least potent, it seemed reasonable to use it as a bench mark of unity. By dividing the dose needed of mescaline (to produce central effects) by the dose needed of another drug, one would generate a number that represented just how many times more potent this new drug was than mescaline. I used this term in a very early review of the one-ring psychotomimetics, and it served satisfactorily for quite a while.

  Its intrinsic worth proved, however, to be its very limitation. It was quickly apparent that the principal value, to behavioral researchers, of the reports of new hallucinogenic drugs, was not in the nature of their action but in the amount of stuff needed to produce that action. This was an essential axis against which the animal pharmacologist could plot his findings. A number was wanted, and the mescaline unit was just that number. Sadly, the major question that is asked by most academic researchers in their evaluation of the psychedelic materials is, RHow much does it take,S

  rather than RWhat does it do.S The marvelous nuances of action, the subtle variations of effect, are dismissed as being hopelessly subjective and thus without scientific worth. But they are, I believe, of great worth. That is exactly what this book is all about.

  179 4-T-TRIS; 4-THIOTRESCALINE; 4-THIOTRISESCALINE; 3,5-DIETHOXY-4-ETHYLTHIOPHENETHYLAMINE

  SYNTHESIS: A solution of 12.1 g N,N,NU,NU-tetramethylethylenediamine and 16.6 g of 1,3-diethoxybenzene was made 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
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  of 1.6 M butyllithium in hexane. The stirred reaction mixture became a little cloudy and then gradually formed a white granular precipitate. This was brought to room temperature, stirred for 0.5 h, and returned again to 0 !C. There was added 12.8 g of diethyl disulfide which seemed to produce an exothermic reaction. After being held for a few min at reflux temperature, the reaction mixture was added to 600 mL dilute H2SO4 which produced two clear phases. The petroleum ether phase was separated, and the aqueous phase extracted with 2x75 mL Et2O. The organics were combined, and the solvents removed under vacuum. There was obtained as residue 24 g of a viscous oil. This was distilled at 93-110 !C at 0.3 mm/Hg yielding 21.5 g 1,3-diethoxy-2-ethylthiobenzene which spontaneously crystallized.

  Grinding under a small amount of hexane, filtering, and hexane washing provided 18.5 g of white crystals with a mp of 26-27 !C. Anal.

  (C12H18O2S) C,H.

  To a stirred solution of 17.3 g of 1,3-diethoxy-2-ethylthiobenzene in 175 mL CH2Cl2 there was added 11.8 g elemental bromine dissolved in 100 mL CH2Cl2. There was an immediate loss of color, and the obvious evolution of HBr gas. After stirring at ambient temperature for 1 h, the dark solution was added to 150 mL H2O containing 1 g of sodium dithionite. Shaking immediately discharged the residual bromine color, and the organic phase was separated, The aqueous phase was extracted once with 75 mL CH2Cl2, the pooled extracts washed first with H2O, and then with saturated brine. Removal of the solvent under vacuum provided 34.2 g of a pale yellow oil with several globs of H2O