Pihkal

by Alexander Shulgin

  Towards the cyclopentyl homologue, a solution of 2,5-dimethoxythiophenol and cyclopentyl bromide in DMSO containing anhydrous potassium carbonate was stirred for several hours at room temperature and yielded 2,5-dimethoxyphenyl cyclopentyl sulfide as a white oil that boiled at 135-145 !C at 0.3 mm/Hg. This was brought to react with a mixture of phosphorus oxychloride and N-methylformanilide producing 2,5-dimethoxy-4-(cyclopentylthio)benzaldehyde as yellow crystals from MeOH. This will some day be converted to the nitrostyrene and then reduced to

  2,5-dimethoxy-4-cyclopentylthiophenethylamine hydrochloride, 2C-T-23.

  48 2C-T-17; NIMITZ; 2,5-DIMETHOXY-4-(s)-BUTYLTHIOPHENETHYLAMINE

  SYNTHESIS: To a solution of 2.6 g of KOH pellets in 50 mL hot MeOH, there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) and 5.8 g (s)-butyl bromide. The reaction was exothermic, with the deposition of white solids. This was heated on the steam bath for a few h, the solvent removed under vacuum, and the resulting solids dissolved in 250 mL H2O. Additional aqueous NaOH

  was added to bring universal pH paper to a full blue color. This was extracted with 3x40 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl (s)-butyl sulfide which was a pale yellow oil, weighing 10.12 g. It was sufficiently pure for use in the next reaction without a distillation step.

  A mixture of 15.1 g POCl3 and 14.1 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 9.4 g of 2,5-dimethoxyphenyl (s)-butyl sulfide, and the mixture heated for 35 min on the steam bath. This was then added to 200 mL of well-stirred warm H2O (pre-heated to 55 !C) and the stirring continued until the oily phase had completely solidified (about 15 min). These light brown solids were removed by filtration, and washed with additional H2O. After sucking as dry as possible, these solids (12.14

  g wet) were ground under an equal weight of MeOH which produced a yellowish crystalline solid with a mp of 76-81 !C. Recrystallization of a 0.4 g sample from an equal weight of boiling MeOH provided 0.27 g of 2,5-dimethoxy-4-(s-butylthio)benzaldehyde as a pale cream-colored crystalline material with a mp of 86-87 !C.

  To a solution of 8.0 g of the crude

  2,5-dimethoxy-4-(s-butylthio)benzaldehyde in 40 g of nitromethane there was added 0.38 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 1 h. The reddish colored solution was decanted from some insoluble tan material and the excess nitromethane removed under vacuum. The heavy red oil that remained was diluted with an equal volume of boiling MeOH, and allowed to return to room temperature. The orange-colored crystals that slowly formed were removed by filtration and, after air drying, weighted 6.24

  g. This was again recrystallized from an equal volume of MeOH, yielding 2,5-dimethoxy-4-(s-butylthio)-'-nitrostyrene as yellow, somewhat beady crystals that weighed (when dry) 3.50 g and which had a mp of 62-65 !C. A small portion of this fraction was crystallized yet again from MeOH to provide an analytical sample that was yellow-orange in color, and had an mp of 68-69 !C. Anal. (C13H17NO4S) C,H.

  A solution of LAH (120 mL of a 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 3.3 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.83 g

  2,5-dimethoxy-4-(s-butylthio)-'-nitrostyrene in 80 mL anhydrous THF

  dropwise over the course of 2 h. 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 18 mL IPA followed first by 5 mL

  of 15% NaOH and then by 15 mL of H2O. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate and washing were combined and stripped of solvent under vacuum providing about 8.5 g of a pale amber oil. Without any further purification, this was distilled at 135-150 !C at 0.4 mm/Hg to give 6.12 g of a clear white oil. This was dissolved in 30 mL IPA, and neutralized with 2.1 mL of concentrated HCl forming crystals immediately. Another 10 mL of IPA was added to allow the solids to be finely dispersed, and then about 100 mL of anhydrous Et2O were added. The solids were removed by filtration, Et2O washed, and air dried to constant weight.

  The product, 2,5-dimethoxy-4-(s)-butylthiophenethylamine hydrochloride (2C-T-17) was obtained as spectacular white crystals, weighing 5.67 g.

  DOSAGE: 60 - 100 mg.

  DURATION: 10 - 15 h.

  QUALITATIVE COMMENTS: (with 60 mg) This material took fully three hours to get into its maximum effect. I never was at a +++, quite, and I am not sure why it is really active, but I know it is. There does not seem to be any interference with my concentration or mental coordination, but I wouldnUt want to drive right now. Good appetite in the evening, for a Chicago-style pizza, and there was no Tomso effects (the rekindling of a psychedelic effect with alcohol) with a glass of wine. An over-all good and instructive ++, no visuals, totally benign. There is no hesitation in doing it again some day.

  (with 100 mg) A small fragment hadnUt dissolved when I drank the solution, and it must have stuck to the back of my mouth, because it made a searing spot that burned for 5 minutes. The first central effects were noted at an hour. The plateau stretched from the 3rd to the 7th hour, then tapered off quite quickly. My sleep was fitful, with some hints of nervous sensitivity. I felt that there were some residuals even into the next morning. A truly heavy psychedelic, but with very few explicit sensual changes or unusual perceptions to justify that comment. Why is it heavy? It just is. This dosage is high enough.

  EXTENSIONS AND COMMENTARY: An interesting, and quite logical, habit that seems to always pop up when a lot of talk and energy become directed at a specific compound, is the habit of using a nickname for it. The Tweetios are an example, and in the 2C-T-X family I had mentioned the term SESQUI. Here, this compound was called NIMITZ, for the obvious reason that the major freeway from Oakland to San Jose, the Nimitz freeway, was also called State Highway 17. Its name has been changed to Interstate 880, and I guess it could now only be used as a reference point if efforts were being made for a 2C-T-880.

  The reason that 2C-T-17 is of special theoretic interest is that it is one of the very first of the active psychedelic compounds (along with 2C-G-5) to have a potential optically active center on the side of the ring away from the nitrogen atom. One of the oldest and best studied variants of the phenethylamine chain are the alpha-methyl homologues, the substituted amphetamines. Here there is an asymmetric carbon atom right next to the amine group, allowing the molecule to be prepared in either a right-hand way or a left-hand way. The RRS or the RSS

  isomer. And in the several studies that have looked at such isomers separately, it has always been the RRS isomer that has carried the psychedelic effects. This probably says something about the nitrogen end, the metabolic end, the RnorthS end of the receptor site that recognizes these compounds, and suggests that there is some intrinsic asymmetry in the area that binds near to the basic nitrogen atom.

  But very little is known of the receptor's RsouthS end, so to speak, the geometry of the area where the opposite end of the molecule has to fit. Here, with 2-C-17, there is a secondary butyl group, and this contains an asymmetric carbon atom. But now this center of asymmetry is clear across the benzene ring from the nitrogen, and should certainly be in some entirely new part of the receptor site. Why not make this compound with the RRS and the RSS forms in this new and unusual location? Why not, indeed! Why not call them the right-lane and the left lane of the Nimitz? Fortunately, both RRS and RSS

  secondary butyl alcohols were easily obtained, and the synthesis given above for the racemic compound was paralleled for each of these isomers, separately. Is there any chemistry that is different with the specific optical isomers from that which has been reported with the racemic? There certainly is for the first step, since the butyl alcohols rather than the butyl bromides must be used, and this first step must go by inversion, and it
cannot be allowed any racemization (loss of the optical purity of the chiral center).

  The synthesis of 2C-T-17 RRS required starting with the RSS isomer of secondary butanol. The RSS 2-butanol in petroleum ether gave the lithium salt with butyllithium which was treated with tosyl chloride (freshly crystallized from naphtha, hexane washed, used in toluene solution) and the solvent was removed. The addition of 2,5-dimethoxythiophenol, anhydrous potassium carbonate, and DMF

  produced RSS 2,5-dimethoxyphenyl s-butyl sulfide. The conversion to RRS 2,5-dimethoxy-4-(s-butyl-thio)benzaldehyde (which melted at 78-79

  !C compared to 86-87 !C for the racemic counterpart) and its conversion in turn to the nitrostyrene, RSS-2,5-dimethoxy-4-(s)-butylthio-'-nitrostyrene which melted at 70-71

  !C compared to 68-69 !C for the racemic counterpart, followed the specific recipes above. The preparation of the intermediates to 2C-T-17 RSS follows the above precisely, but starting with RRS

  2-butanol instead. And it is at these nitrostyrene stages that this project stands at the moment.

  It would be fascinating if one of the two optically active 2C-T-17Us carried all of the central activity, and the other, none of it. What is more likely is that the spectrum of effects will be teased apart, with one isomer responsible for some of them and the other isomer responsible for the others. Then, again, maybe the south end of the receptor site in the brain is totally symmetric, and the two optical antipodes will be indistinguishable.

  An incidental bit of trivia Q yet another bit of evidence that we are all totally asymmetric in our personal body chemistry. RRS and RSS

  secondary butanols smell different. The RRS has a subtle smell, which is rather fragrant . The RSS is stronger, hits the nasal passages harder, and reminds one of isopropanol more than does the RSS isomer.

  49 2C-T-21; 2,5-DIMETHOXY-4-(2-FLUOROETHYLTHIO)PHENETHYLAMINE

  SYNTHESIS: To a solution of 6.9 g of KOH pellets in 100 mL hot MeOH, there was added 13.0 g 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) followed by 9.6 g 2-fluoroethyl bromide. The reaction was exothermic, with the immediate deposition of white solids. This was allowed to stand for 2 h, added to 1 L H2O, and extracted with 3x75 mL CH2Cl2. The extracts were pooled and the solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl 2-fluoroethyl sulfide which was a colorless oil and weighed 17.2 g.

  It was sufficiently pure for use in the next reaction without a distillation step.

  A mixture of 26.8 g POCl3 and 24.8 g N-methylformanilide was heated for 10 min on the steam bath. To this claret-colored solution was added 17.0 g of 2,5- dimethoxyphenyl 2-fluoroethyl sulfide, and the mixture heated an additional 25 min on the steam bath. This was then added to 1.5 L of well-stirred warm H2O (pre-heated to 55 !C) and the oily phase that formed solidified almost immediately. This brown sugar-like product was removed by filtration, and washed with additional H2O. After sucking as dry as possible, the residual solids (weighing 19.0 g wet) were dissolved in an equal weight of boiling MeOH which, after cooling in an ice-bath, deposited pale ivory colored crystals of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde. This was air dried to constant weight, which was 15.1 g.

  To a solution of 15.0 g 2,5-dimethoxy-(2-fluoroethylthio)benzaldehyde in 75 mL nitromethane there was added 1.35 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 70 min (the progress of the reaction must be followed by continuous TLC

  monitoring). The clear deeply-colored solution was decanted from some insoluble material and the excess nitromethane removed under vacuum.

  There resulted 17.78 g of almost dry brick-red crystals which were dissolved in 110 mL boiling EtOAc. After cooling overnight in the refrigerator, the crystalline product was removed, washed with EtOAc, and air dried. There was obtained 14.33 g of 2,5-dimethoxy-4-(2-fluoroethylthio)-'-nitro-styrene as bright orange crystals.

  A solution of LAH (140 mL of a 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 3.7 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 8.9 g

  2,5-dimethoxy-4-(2-fluoroethylthio)-'-nitrostyrene in 40 mL of hot anhydrous THF (a heat lamp was needed to keep the nitrostyrene in solution). As the nitrostyrene entered the hydride solution, there was an immediate loss of color. After 1 h stirring at room temperature, the temperature was brought up to a gentle reflux on the steam bath, then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of 15 mL IPA and the inorganic solids were made white and filterable by the addition of 15 ml 15%

  NaOH. The loose cottage-cheesy solids were removed by filtration, and washed with additional THF. The filtrate and washes were pooled and stripped of solvent under vacuum providing 7.39 g of a pale amber oil.

  This was dissolved in 600 mL dilute H2SO4, and washed with 3x50 mL

  CH2Cl2 (which removed the light yellow color). The aqueous phase was made strongly basic with 25% NaOH, extracted with 3x75 mL CH2Cl2 and, after pooling, the solvent was removed under vacuum leaving 4.91 g of product as an oil. This was distilled at 145-160 !C at 0.4 mm/Hg giving 3.91 g of a white oil. This was dissolved in 40 mL IPA and neutralized with 35 drops of concentrated HCl. The beautiful white solids that formed were removed by filtration, and washed with IPA.

  All were suspended in, and ground under, 40 mL anhydrous Et2O, refiltered and air dried. The final weight of 2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine hydrochloride (2C-T-21) was 4.07 g of glistening white crystals.

  DOSAGE 8 - 12 mg.

  DURATION: 7 - 10 h.

  QUALITATIVE COMMENTS: (with 6 mg) I noticed something undefined within five minutes which went away. Within 15 minutes I noticed a definite awareness of activity. There was a progressive increase in awareness of something happening over the next two hours with a plateau of perhaps an hour then occurring. The nature of the happening, as usual, was not clear. During the experience I was more talkative than I usually am. I seemed to be interacting with all others. There was no euphoria but, then, there was no body load or nausea, nor was there any nystagmus. I found a little mental confusion at the peak and there was some searching in my memory bank for the right chips at times. I lost the entire line of one of my conversations at one point during the plateau and had to ask what I was talking about. I tested my visual field on a painting and with sufficient concentration I could get the center part to wiggle a little. I didnUt try to observe anything with my eyes closed. I feel that there was something physical about the eyes. In the evening, after-images were quite intense, and the next day my eyes seemed tired or bothered. What can I say? The material was pleasant and I certainly got the feeling of being high but not getting too much out of it. There were no insights or Rah-hahs.S I wonder if periodic and frequent use (say twice a day) at the one or two milligram level would be a positive mood enhancer?S

  (with 8 mg) Comes on very gradually and slowly. Takes about an hour to feel. Reasonably intense in two hours, ++. Very pleasant material, enhancing communication, clear thinking, good feeling.

  There is a feeling of closeness; the bondedness with the group grows steadily during the day, reaching a highly rewarding level. For me a couple of firsts regarding food. I was hungry only two hours into it.

  I usually donUt want food 'til well down as I usually feel that it interferes with the experience. And, also, I nibbled constantly as I felt that there was nothing in my body. And I enjoyed it thoroughly, feeling only the warmth and energy, with no contrary developments.

  There was a nice feeling of inner strength and peace.

  (with 8 mg) It was very difficult to fix the times of ascent or descent. Some chilling during onset but not later. And there was some yawning and ear-popping. It is easy on the body, in no way threatening. This time I am very relaxed and somewhat lethargic; the visuals are not too pronounced. Excellent sleep.

  (with 10 mg) I find I can use it if I set my energy in a direction I really want to go in. Otherwise I can just be s
toned and self-indulgent. Not out-of-body cosmic at all. But it's good material, an ally, not presenting hidden negatives.

  (with 12 mg) Well ... 12 milligrams is quite enough for a +3, which was established within the first hour and plateauUd by the end of the second. Body felt quite safe, again, but there was considerable push of energy. I did not feel par-ticularly interested in doing anything like writing and in fact preferred to watch television while rocking a bit on the couch, to ease the push. Mood was faintly grim, but not more than faintly. I noted something that I hadnUt seen before with this material: time slowing. The first two hours seemed to last a very long time. There was no anorexia. It wasnUt until 10 PM [fifth hour] that the idea of writing had any appeal at all. By then, I was still +3 but a lot more at ease. I wrote two letters and enjoyed the process. Sleep was fine. My mood next day was slightly introverted, not very spontaneous for a while. Late in the afternoon, it was a lot better.

  EXTENSIONS AND COMMENTARY: This is about as potent a phenethylamine as they come. There are a couple in the 2C-G family that are similar in potency, but they are much longer lived. The motivation for the use of the beta-fluoroethyl group can be seen under the discussion of DOEF, where there was an amalgamation of two lines of reasoning: the imitation of potent serotonin agonists with a need of including an atom (the fluorine) that is potentially labelable with a positron emitter. And the mass-18 isotope of fluorine, with a half-life of just under 2 hours, is ideal for many biological studies. In fact, much of the research work being carried out by the Nuclear Medicine group in Berkeley is based on the analogy between a halogen atom and a beta-fluoroethyl group. There are some similarities in pharmacology so that if there is a bromine or an iodo atom present in a drug, it is a fair guess that the corresponding beta-fluoroethyl would also be active. In a sense, the cute (and chemically impossible) idea of putting a bromo atom on the sulfur of the 2C-T family is nicely satisfied by using the beta-fluoroethyl group instead (which is chemically completely possible).