Pihkal

by Alexander Shulgin

  DOSAGE: above 30 mg.

  DURATION: 6 - 10 h.

  QUALITATIVE COMMENTS: (with 20 mg) There was a gentle and demanding rise from the one to the three hour point that put me into an extremely open, erotic, and responsive place. I had to find a familiar spot to orient myself, and the kitchen served that need. As the experience went on, it showed more and more of a stimulant response, with tremor, restlessness, and a bit of trouble sleeping.

  But there was no anorexia! An OK experience.

  (with 30 mg) There is a real physical aspect to this, and I am not completely happy with it. There is diarrhea, and I am restless, and continuously aware of the fact that my body has had an impact from something. The last few hours were spent in talking, and I found myself still awake some 24 hours after the start of the experiment.

  The mental was not up there to a +++, and yet the physical disruption was all that I might care to weather, and exceeds any mental reward.

  When I did sleep, my dreams were OK, but not rich. Why go higher?S

  EXTENSIONS AND COMMENTARY: This is another example of the N-methyl homologues of the psychedelics. None of them seem to produce stuff of elegance. It is clear that the adding of an N-methyl group onto DOM

  certainly cuts down the activity by a factor of ten-fold, and even then results in something that is not completely good. Three milligrams of DOM is a winner, but even ten times this, thirty milligrams of N-methyl-DOM, is somewhat fuzzy. In the rabbit hyperthermia studies, this compound was some 25 times less active than DOM, so even animal tests say this is way down there in value. This particular measure suggests that the active level in man might be 75

  milligrams. Well, maybe, but I am not at all comfortable in trying it at that level. In fact I do not intend to explore this any further whatsoever, unless there is a compelling reason, and I see no such reason. For the moment, let us leave this one to others, who might be more adventurous but less discriminating.

  In browsing through my notes I discovered that I had made another N-substitution product of DOM. Efforts to fuse free-base DOM with the ethyl cyclopropane carboxylate failed, but the reaction between it and the acid chloride in pyridine gave the corresponding amide, with a mp of 156-157 !C from MeOH. Anal. (C16H23NO3) C,H,N. This reduced smoothly to the corresponding amine,

  N-cyclopropyl-2,5-dimethoxy-4-methylamphetamine which formed a hydrochloride salt melting at 153-156 !C. I canUt remember the reasoning that led to this line of synthesis, but it must not have been too exciting, as I never tasted the stuff.

  12 BIS-TOM; 4-METHYL-2,5-bis-(METHYLTHIO)AMPHETAMINE

  SYNTHESIS: A solution of 9.0 g 2,5-dibromotoluene in 50 mL petroleum ether was magnetically stirred under a He atmosphere. To this there was added 50 mL of a 1.6 M hexane solution of butyllithium, and the exothermic reaction, which produced a granular precipitate, was allowed to stir for 12 h. The mixture was cooled to 0 !C and there was then added 7.5 g dimethyldisulfide. There was a heavy precipitate formed, which tended to become lighter as the addition of the disulfide neared completion. After 20 min additional stirring, the reaction mixture was poured into H2O that contained some HCl. The phases were separated and the aqueous phase extracted with 50 mL Et2O.

  The organic phase and extract were combined, washed with dilute NaOH, and then with H2O. After drying over anhydrous K2CO3, the solvent was removed under vacuum and the residue distilled to give a fraction that boiled at 75-85 !C at 0.3 mm/Hg and weighed 5.3 g. This was about 80%

  pure 2,5-bis-(methylthio)toluene, with the remainder appearing to be the monothiomethyl analogues. A completely pure product was best obtained by a different, but considerably longer, procedure. This is given here only in outline. The phenolic OH group of 3-methyl-4-(methylthio)phenol was converted to an SH group by the thermal rearrangement of the N,N-dimethylthioncarbamate. The impure thiophenol was liberated from the product N,N-dimethylthiolcarbamate with NaOH treatment. The separation of the phenol/thiophenol mixture was achieved by a H2O2 oxidation to produce the intermediate 3-methyl-4-methylthiophenyldisulfide. This was isolated as a white crystalline solid from MeOH, with a mp of 78-79 !C. Anal. (C16H18S4) C,H. It was reduced with zinc in acetic acid, and the resulting thiophenol (a water-white liquid which was both spectroscopically and microanalytically correct) was methylated with methyl iodide and KOH

  in MeOH to give the desired product, 2,5-bis-(methylthio)toluene, free of any contaminating mono-sulfur analogues.

  A solution of 3.9 g of 2,5-bis-(methylthio)toluene in 20 mL acetic acid was treated with a crystal of iodine followed by the addition of 3.5 g elemental bromine. This mixture was heated on the steam bath for 1 h, which largely discharged the color and produced a copious evolution of HBr. Cooling in an ice bath produced solids that were removed by filtration. Recrystallization from IPA gave 1.9 g of 2,5-bis-(methylthio)-4-bromotoluene as a white crystalline solid with a mp of 133-134 !C. Anal. (C9H11BrS2) C,H. An alternate synthesis of this intermediate was achieved from 1,4-dibromobenzene which was converted to the 1,4-bis-(methylthio)benzene (white crystals with a mp of 83.5-84.5 !C) with sodium methylmercaptide in hexamethylphosphoramide. This was dibrominated to 2,5-dibromo-1,4-bis-(methylthio)benzene in acetic acid (white platelets from hexane melting at 195-199 !C). This, in Et2O solution, reacted with BuLi to replace one of the bromine atoms with lithium, and subsequent treatment with methyl iodide gave 2,5-bis-(methylthio)-4-bromotoluene as an off-white solid identical to the above material (by TLC and IR) but with a broader mp range.

  A solution of 2.4 g 2,5-bis-(methylthio)-4-bromotoluene in 100 mL

  anhydrous Et2O, stirred magnetically and under a He atmosphere, was treated with 10 mL of a 1.6 M solution of butyllithium in hexane.

  After stirring for 10 min there was added 2.5 mL N-methylformanilide which led to an exothermic reaction. After another 10 min stirring, the reaction mixture was added to 100 mL dilute HCl, the phases were separated, and the aqueous phase extracted with 2x50 mL Et2O. The combined organic phase and extracts were dried over anhydrous K2CO3, and the solvent removed under vacuum. The partially solid residue was distilled at 140-150 !C at 0.2 mm/Hg to give a crystalline fraction that, after recrystallization from 15 mL boiling IPA gave 2,5-bis-(methylthio)-4-methylbenzaldehyde as a yellow-brown solid which weighed 1.1 g and had a mp of 107-109 !C. An analytical sample from MeOH melted at 110-111 !C with an excellent IR and NMR. Anal.

  (C10H12OS2) C,H. An alternate synthesis of this aldehyde employs the 2,5-bis-(methylthio)toluene described above. A CH2Cl2 solution of this substituted toluene containing dichloromethyl methyl ether was treated with anhydrous AlCl3, and the usual workup gave a distilled fraction that spontaneously crystallized to the desired aldehyde but in an overall yield of only 11% of theory.

  To a solution of 0.5 g 2,5-bis-(methylthio)-4-methylbenzaldehyde in 15

  mL nitroethane there was added 0.15 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 1 h. The excess solvent was removed under vacuum and the residue was dissolved in 10 mL

  boiling MeOH. This solution was decanted from a little insoluble residue, and allowed to cool to ice bath temperature yielding, after filtering and drying to constant weight, 0.55 g of 1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene as pumpkin-colored crystals with a mp of 90-91 !C. This was not improved by recrystallization from EtOH. Anal. (C12H15NO2S2) C,H.

  A cooled, stirred solution of 0.5 g LAH in 40 mL THF was put under an inert atmosphere, cooled to 0 !C with an external ice bath, and treated with 0.42 mL 100% H2SO4, added dropwise. A solution of 0.5 g 1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene in 20 mL

  anhydrous THF was added over the course of 5 min, and the reaction mixture held at reflux for 30 min on the steam bath. After cooling again to ice temperature, the excess hydride was destroyed by the addition of IPA and the inorganics were converted to a loose, white filterable form by the addition of 1.5 mL 5% NaOH. These solids were removed by filtration and the filter cake was washed with 2x50 mL IPA.

 
The combined filtrate and washings were stripped of solvent under vacuum to give a residue that was a flocculant solid. This was suspended in dilute H2SO4 and extracted with 2x50 mL CH2Cl2, and the combined organics extracted with 2x50 mL dilute H3PO4. The aqueous extracts were made basic, and the product removed by extraction with 2x75 mL CH2Cl2. After removal of the solvent under vacuum, the residue was distilled at 126-142 !C at 0.2 mm/Hg to give 0.2 g of product which crystallized in the receiver. This was dissolved in 1.5

  mL hot IPA, neutralized with 4 drops of concentrated HCl, and diluted with 3 mL anhydrous Et2O to give, after filtering and air drying, 0.2

  g. of 2,5-bis-(methylthio)-4-methylamphetamine hydrochloride (BIS-TOM) as white crystals with a mp of 228-229 !C. Anal. (C12H20ClNS2) C,H.

  DOSAGE: greater than 160 mg.

  DURATION: unknown.

  QUALITATIVE COMMENTS: (with 160 mg) I was vaguely aware of something in the latter part of the afternoon. A suggestion of darting, physically (when going to sleep), but nothing at the mental level.

  This is as high as I will go.

  EXTENSIONS AND COMMENTARY: It is reasonable, in retrospect, to accept that BIS-TOM is not an active compound. The replacement of the 2-position oxygen of DOM with a sulfur atom (to give 2-TOM) dropped the potency by a factor of 15x, and the replacement of the 5-position oxygen with a sulfur atom (to give 5-TOM) dropped the potency by a factor of about 10x. It would be a logical calculation that the replacement of both oxygen atoms with sulfur might drop the potency by a factor of 150x. So, with DOM being active at maybe 5 milligrams, a logical prediction of the active level of BIS-TOM would be 750

  milligrams. And maybe this would be the right level, but with the hints of neurological disturbance that seemed to be there at 160 mg, there was no desire to go up by a factor of five again. The rewards would simply not be worth the risks.

  The 2-carbon analogue, 2C-BIS-TOM, was prepared from the intermediate aldehyde above, first by reaction with nitromethane to give the nitrostyrene as tomato-colored crystals from EtOAc, mp 145-146 !C.

  Anal. (C11H13NO2S2) C,H. This was reduced with AH to give 2,5-bis-(methylthio)-4-methylphenethylamine hydrochloride as ivory-colored crystals with a mp of 273-277 !C.

  Although there are many interesting psychedelic drugs with sulfur atoms in them (the TOMUs, the TOETUs, the ALEPH's and all of the 2C-TUs), there just arenUt many that contain two sulfur atoms.

  BIS-TOM bombed out, and 2C-BIS-TOM remains untried, but will probably also fail, as the phenethylamines are rarely more potent than the corresponding amphetamines. This leaves 2C-T-14 as the remaining hope, and its synthesis is still underway.

  13 BOB; '-METHOXY-2C-B; 4-BROMO-2,5-'-TRIMETHOXYPHENETHYLAMINE

  SYNTHESIS: To a vigorously stirred suspension of 2.1 g 4-bromo-2,5-dimethoxy-'-nitrostyrene [from 4-bromo-2,5-dimethoxybenzaldehyde and nitromethane in acetic acid with ammonium acetate as a catalyst, mp 157-158 !C, anal. (C10H10BrNO4) C,H] in 20 mL anhydrous MeOH, there was added a solution of sodium methoxide in MeOH (generated from 0.5 g metallic sodium in 20 mL

  anhydrous MeOH). After a few min there was added 10 mL acetic acid (no solids formed) followed by the slow addition of 50 mL of H2O. A cream-colored solid was produced, which was removed by filtration and washed well with H2O. After air drying the product, 1-(4-bromo-2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane, weighed 2.0

  g. An analytical sample from MeOH was off-white in color and had a mp of 119-120 !C. Anal. (C11H14BrNO5) C,H.

  A solution of LAH (15 mL of 1 M solution in THF) was diluted with an equal volume of anhydrous THF, and cooled (under He) to 0 !C with an external ice bath. With good stirring there was added 0.38 mL 100%

  H2SO4 dropwise, to minimize charring. This was followed by the addition of 1.0 g

  1-(4-bromo-2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane as a solid over the course of 5 min. After an hour of stirring at 0 !C, the temperature was brought up to a gentle reflux on the steam bath for 30

  min. There was no vigorous exothermic reaction seen, unlike that with the syntheses of BOD, BOH and BOM. The reaction mixture was cooled again to 0 !C, and the excess hydride was destroyed by the cautious addition of IPA. This was followed by sufficent dilute aqueous 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 fol-lowed by IPA. The combined filtrate and washings were stripped of solvent under vacuum and dissolved in dilute H2SO4, with the apparent generation of yellow solids. This was washed with 2x50 mL CH2Cl2, and the aqueous phase made basic with NaOH. This was extracted with 2x50 mL CH2Cl2, and the pooled extracts were stripped of solvent under vacuum. The residue was distilled at 130-150 !C at 0.2 mm/Hg to give 0.2 g of product as a clear white oil. This fraction was dissolved in 10 mL IPA, and neutralized with 4 drops concentrated HCl. The addition of 30 mL

  anhydrous Et2O allowed the formation of 4-bromo-2,5,'-trimethoxyphenethylamine hydrochloride (BOB) as a fine white crystalline product. This was removed by filtration, washed with Et2O, and air dried. There was obtained 0.1 g white crystals with a mp of 187-188 !C. Anal. (C11H17BrClNO3) C,H.

  DOSAGE: 10 - 20 mg.

  DURATION: 10 - 20 h.

  QUALITATIVE COMMENTS: (with 10 mg) I donUt know if it was me this day, or if it was the chemical, but I got into a granddaddy of a paranoid, sociopathic snit, without feeling and without emotion. I was indifferent to everything. Later on, there was some improvement, with body tingling (good, IUm pretty sure) and a sense of awareness (good, I guess) but I still canceled my evening dinner company. All in all, pretty negative.

  (with 10 mg) I had to get away and into myself, so I weeded in the vegetable garden for almost an hour. Then I lay down in the bedroom, and enjoyed a magnificent vegetable garden, in Southern France, in my mind's eye. An extraordinary zucchini. And the weeds had all been magically pulled. In another couple of hours a neurological over-stimulation became apparent, and I spent the rest of the day defending myself. In the evening, I took 100 milligrams phenobarbital which seemed to smooth things just enough. Too bad. Nice material, otherwise.

  (with 15 mg) The erotic was lustful, but at the critical moment of orgasm, the question of neurological stability became quite apparent.

  Does one really let go? Everything seemed a bit irritable. The tinnitus was quite bad, but the excitement of the rich altered place I was in was certainly worth it all. Through the rest of the day, I became aware of how tired I was, and how much I wanted to sleep, and yet how scared I was to give myself over to sleep. Could I trust the body to its own devices without me as an overseeing caretaker? LetUs risk it. I slept. The next day there was a memory of this turmoil.

  Clearly the first part of the experience might have been hard to define, but it was quite positive. But the last part makes it not really worth while.

  EXTENSIONS AND COMMENTARY: This compound, BOB, is the most potent of the BOX series. And yet, as with all of the members of this family, there are overtones of physical concern, and of some worry as to the integrity of the body. There may well be a separation of activity with the two optical isomers, but there is not a tremendous push to explore this particular family much further. They canUt all be winners, I guess. What would be the activities of compounds with a sulfur instead of an oxygen at the beta-oxygen position? What would be the nature of action if there were an alpha-methyl group, making all of these into amphetamine derivatives? Or what about both a sulfur and a methyl group? And what about the isomers that are intrinsic to all of this, the threo- and the erythro- and the RDUsS

  and the RLUsS? All this is terra incognita, and must someday be looked into. It is chemically simple, and pharmacologically provocative. Someone, somewhere, someday, answer these questions!

  14 BOD; '-METHOXY-2C-D; 4-METHYL-2,5,'-TRIMETHOXYPHENETHYLAMINE

  SYNTHESIS: A solution of 39.6 g

  1-(2,5-dimethoxy-4-methylphenyl)-2-nitrostyrene (see recipe for 2C-D

 
for its preparation) in 300 mL warm MeOH was prepared. Separately, a solution of 9 g elemental sodium in 150 mL MeOH was also prepared.

  This sodium methoxide solution was added to the well-stirred nitrostyrene solution, which resulted in a dramatic loss of color.

  There was then added 75 mL acetic acid, and all was poured into 2 L

  H2O. This was extracted with 3x100 mL CH2Cl2. The pooled extracts were stripped of solvent, and the 35 g of residue was treated with 5

  mL MeOH, allowed to stand for a short while, decanted from some insoluble residue, and the separated clear solution kept at 0 !C

  overnight. There was the deposition of a yellow crystalline product which, after removal by filtration and air drying, weighed 9.7 g.

  Recrystallization from 25 mL MeOH gave, after filtering and drying, 8.4 g of canary-yellow crystals of

  1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane with a mp of 78-79 !C. Evaporation of the mother liquors from the filtration of the first crop yielded 3.8 g of additional product which, upon recrystallization from 11 mL MeOH, provided another 2.7 g with a mp of 77-78 !C. Further workup of the mother liquors yielded only impure starting nitrostyrene.

  A solution of LAH (96 mL of 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 2.4 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 10.8 g

  1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane. There was immediate discoloration. After the addition was complete, the reaction mixture was held at reflux on the steam bath for 2 h. After cooling again, the excess hydride was destroyed with 4 mL IPA and the reaction mixture made basic with 15% NaOH. The insoluble inorganic salts were removed by filtration, and the filter cake was washed first with THF, and then with IPA. The bright yellow filtrate and washes were pooled and stripped of solvent under vacuum, yielding 14 g of a yellow oil. This was suspended in 1 L dilute H2SO4 to give an ugly, cloudy, yellow-orange mess. Extraction with 3x75 mL CH2Cl2 removed much of the color, and the remaining aqueous phase was made basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2. Evaporation of the solvent under vacuum gave 9 g of a pale amber oil which was distilled at 115-130 !C at 0.4 mm/Hg. The water-white distillate was dissolved in 15 mL IPA, neutralized with concentrated HCl, and then diluted with 70 mL anhydrous Et2O. After a few min, white crystals formed, and these were removed by filtration and Et2O washed. When air-dried to constant weight, 4.49 g brilliant white crystals of 4-methyl-2,5,'-trimethoxyphenethylamine hydrochloride (BOD) with a mp of 171-172 !C with decomposition, were obtained. The mother liquors on standing deposited 0.66 g additional crystals which were impure and were discarded. Anal. (C12H20ClNO3) C,H.