Pihkal

by Alexander Shulgin

  A logical extension of 2C-T-21 is the three carbon amphetamine analogue which should be, by comparing structures and activities, a very potent and in-teresting material in its own rights. This would be 2,5-dimethoxy-4-(2-fluoroethylthio)amphetamine or, following the nomenclature used with the earlier members of this series, ALEPH-21.

  A solution of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde (see earlier in this recipe) in nitroethane with ammonium acetate gave 1-(2,5-dimethoxy-4-(2-fluoroethylthio)phenyl)-2-nitropropene as yellow-orange crystals from MeOH with a melting point of 102-104 !C.

  And that is where the project now stands. It has not yet been reduced to the amine.

  This phenethylamine, 2C-T-21, was the last of the 2C-T's to be completed. A couple of other sulfur analogues have been given numbers, and have been started, but the syntheses are still at some intermediate state.

  The (n)-butyl compound, named 2C-T-19, has been taken to the nitrostyrene stage. Reaction between 2,5-dimethoxythiophenol and (n)-butylbromide with KOH gave 2,5-dimethoxyphenyl (n)-butyl sulfide as a colorless oil. This, with phosphorus oxychloride and N-methylformanilide, provided

  2,5-dimethoxy-4-(n-butylthio)benzaldehyde as pale orange solids from MeOH, with a melting point of 78-79 !C. This, with nitromethane and ammonium acetate, gave 2,5-dimethoxy-4-(n-butylthio)-'-nitrostyrene, with a melting point of 133-134 !C from either IPA or acetonitrile.

  The 2,2,2-trifluoroethyl compound, which I have named 2C-T-22, has been taken to the benzaldehyde stage. Reaction between 2,5-dimethoxythiophenol and 2,2,2-trifluoroethyliodide with KOH gives 2,5-dimethoxyphenyl 2,2,2-trifluoroethyl sulfide as a very pale amber oil. This, with phosphorus oxychloride and N-methylformanilide provided 2,5-dimethoxy-4-(2,2,2-trifluoroethyl)benzaldehyde as crystals that proved to be exceedingly difficult to purify. Yellow solids can be obtained from several solvents, and they melt in the 70

  !C area. The initially isolated fraction melted at 69-72 !C and showed three major spots by both TLC and GCMS. The largest GC peak was the correct product with a parent peak of 280 m/e, and cracking fragments at 154 and 234 m/e. A small sample was finally obtained from hexane with a melting point of 78-79 !C but I am not sure that even it is particularly pure. Not surprisingly, the reaction of this crude benz-aldehyde with nitromethane and ammonium acetate gave a nitrostyrene product that was a complex mixture. And there that project also rests.

  A couple of additional efforts warrant comment. The reaction between trifluoromethyliodide and 2,5-dimethoxythiophenol should have produced 2,5-dimethoxyphenyl trifluoromethyl sulfide, but it didnUt produce anything. And one more. What about a bare thio group at the 4-position in this 2C-T-family? Maybe this can be protected through everything as the disulfide, and be reduced at the last step! The disulfide, 2,5-dimethoxyphenyl disulfide (see under 2C-T-15) was aimed towards the needed bis-aldehyde with phosphorus oxychloride and N-methylformanilide, but all that came out of this were black oils and tars. This has also been abandoned for now.

  And it has just occurred to me that there is yet another effort that is certain-ly worth making, inspired by the observation that 2,2-difluoroethyl iodide is commercially available and not prohibitively expensive. It, with 2,5-dimethoxythiophenol, and following the obvious steps to the aldehyde, the nitrostyrene, and the final amine, would produce

  2,5-dimethoxy-4-(2,2-difluoroethylthio)phenethylamine hydrochloride.

  It lies exactly half way between the highly potent 2C-T-21 (the mono-fluoro), and the yet to be finished 2C-T-22 (the trifluoro).

  Let's be weird, and call it 2C-T-21.5. I will wager mucho that it will be very potent.

  50 4-D; 3,5-DIMETHOXY-4-TRIDEUTEROMETHOXY-PHENETHYLAMINE

  SYNTHESIS: To a solution of 34.0 g homosyringonitrile (3,5-dimethoxy-4-hydroxyphenylacetonitrile, see under ESCALINE for its preparation) in 350 mL acetone containing 0.5 g decyltriethylammonium iodide, there was added 25 g trideuteromethyl iodide followed by 50 g of finely powdered anhydrous K2CO3. This mixture was held at reflux on a steam bath for 12 h, added to 2 L of dilute HCl, and extracted with 3x100 mL of CH2Cl2. The extracts were washed with 5% NaOH, and the solvent removed under vacuum, yielding 28.0 g yellow solids.

  These were distilled at 135-150 !C at 0.5 mm/Hg providing 19.4 g 3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile which melted at 76.5-77.5 !C after crystallization from toluene, or 77-78 !C from methylcyclohexane/CHCl3 3:1. The mp of the proteo-reference compound, from toluene, was 77-78.5 !C. The OCD3 stretch in the infra-red occured at 2072 cm-1.

  A solution of 275 mL of 1.0 M LAH in THF was cooled under He to 0 !C

  and treated with 7.25 mL 100% H2SO4 added very slowly with vigorous stirring. A solution of 19.3 g

  3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile in 200 mL

  anhydrous THF was added slowly, and following the addition stirring was continued for 20 min. The reaction mixture was brought to a reflux for 30 min on a steam bath, cooled again to 0 !C, and the excess hydride destroyed with 25 mL IPA. About 15 mL of 15% NaOH was required to convert the solids to a filterable white consistency.

  These were removed by filtration, the cake washed with IPA, the filtrates and washes were combined, and the solvent removed under vacuum leaving a white oil as residue. This was dissolved in 1.5 L

  dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with 3x75 mL CH2Cl2. Removal of the solvent from these extracts under vacuum yielded 18.5 g of a colorless oil which was distilled at 120-150 !C at 0.5 mm/Hg to provide 13.5 g of a white oil. This was dissolved in 70 ml IPA and neutralized with concentrated HCl, producing spontaneous crystals. These were removed by filtration, washed first with IPA then with anhydrous Et2O. After air drying, the final yield of

  3,5-dimethoxy-4-trideuteromethoxyphenethylamine hydrochloride (4-D) was 13.50 g.

  DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the hydrochloride salt).

  DURATION: 12 h.

  QUALITATIVE COMMENTS: (with 275 mg) The onset was smooth and gradual.

  Within the hour, the slight queasiness I experienced (not as much as with mescaline) completely disappeared. Some visual enhancement, good energy, good communication. It was a very special day for me as I was in a good place pretty much the whole day, and able to communicate clearly without deeper feelings getting in the way. While most enjoyable, and at times remarkable fun, I did not experience the intensity I am familiar with, with mescaline.

  (with 300 mg) The taste was bitter to a moderate degree but faded fast. About 40 minutes later the first stirrings of pleasurable experience came on. It was very mild. Twenty minutes after that an unease of the stomach was apparent, and it stayed with me until I ate some crackers an hour or so later. I got no sharpened visual reactions and no physical instability at any time. I did feel a quickening of thought and verbal flow; again, this was mild and unlike my earlier mescaline patter.

  (with 350 mg) A rapid onset Q alert in 20 minutes. Climbed to a plus two in about one hour and stayed there. During the first two hours had a slight queasiness or pre-nausea, and cold hands and feet, but this all disappeared completely and I became very hungry during the whole latter half of the experience. I did not eat much at any one time, but did a lot of snacking and everything tasted good. Very pleasant after the plateau was reached. Pretty good visuals with eyes closed, but not as bright as 2C-B. Very little visuals with eyes open Q some movement and flow of objects Q pupils dilated. Spent most of the day lying down Q had no aversion to conversation but it felt good just to be still. I was in a funny place I canUt quite describe Q I was in an 'alert lassitude,' a state of 'interested detachment,' or a place of 'vibrating equanimity' or whatever. While trying to recapture the day, it seemed to me that it was a good day, but that nothing much had really transpired. However, upon reflection, I am startled to find that several important shifts took place. It was a day that allowed some peaceful gear-shifting in the mind.

  (with 400 mg) Not a great taste. Some type of awareness at app
rox.

  20 minutes. Considerable nausea peaking at about 1 hr. Some nausea continued through the experience but became quite low. I enjoyed the color show considerably. Trees outside would change color in a wave-like manner. The book-covers upstairs would also change colors and become distorted. Brightly lighted items would undergo the same thing. Believed I could suppress the vision, but concentrating on something would cause it to easily undergo the color and visual changes. Evidently I had little problem following the conversation downstairs, but I remained somewhat quiet. Had an element of confusion that seemed to last for some 4 or 5 hours. Had no problems dropping off to sleep that evening.

  EXTENSIONS AND COMMENTARY: The effects of 4-D and '-D are similar to one-another, both as to dosage and effect. And with both, there is a close parallel to those reported from mescaline. It is reasonable to assume that the human body handles these materials in the same manner, although no metabolic studies have ever been published.

  A similar deuterium substitution pattern is of course completely feasible with TMA and related 3,4,5-trimethoxy-substituted analogues.

  Some studies have supported the idea that the ability to remove methyl groups from such aromatic ethers might be correlated to endogenous schizophrenia. It is possible to imagine that, in such individuals, the effects of substituting trideuteromethyl groups for normal methyl groups might result in psychopharmacological differences of action.

  Two reports exist that describe metabolic products of mescaline that have lost this methyl group on the 4-position oxygen. It is possible that these might be produced in abnormal quantities in mentally ill subjects. There are also similar reports of the 3-methoxyl group being demethylated in man. Here, studies with 3,5-D

  (3,5-bis-trideuteromethoxy-4-methoxyphenethylamine) might reveal some differences in quantitative responses in man. These are extremely minor metabolites, however. I suspect that more extensive studies will establish that 4-D, 3,5-D and '-D all have properties indistinguishable from one-another, at least in healthy subjects.

  51 '-D; 3,4,5-TRIMETHOXY-','-DIDEUTEROPHENETHYLAMINE

  SYNTHESIS: To a solution of 13.6 g homosyringonitrile (see under ESCALINE for its preparation) in 150 mL acetone containing 200 mg decyltriethylammonium iodide and 30 g of finely powdered anhydrous K2CO3, there was added 20 g methyl iodide. The mixture was held at reflux for 18 h in a heating mantle with effective stirring. This was added to 1 L H2O, acidified with concentrated HCl, and extracted with 3x75 mL CH2Cl2. The extracts were pooled, washed with 2x100 mL 5%

  NaOH, once with dilute HCl, once with saturated brine, and the solvent was removed under vacuum. The pale yellow residue was distilled at 130-150 !C at 0.3 mm/Hg to yield 12.9 g of 3,4,5-trimethoxyphenylacetonitrile as an off-white solid. Upon crystallization from methylcyclohexane/CHCl3 it was white and had a mp of 77-78 !C. Attempts to prepare this compound by the theoretically appealing route from 3,4,5-trimethoxybenzaldehyde to N,N-dimethyl-3,4,5-tri-methoxybenzylamine (reductive amination with dimethylamine), to 3,4,5-trimethoxy-N,N,N-trimethylbenzylammonium iodide (methylation with methyl iodide), and then to 3,4,5-

  trimethoxyphenylacetonitrile (with some source of cyanide ion) gave excellent yields in the first two steps, and no product at all in the last step.

  A solution of 20.6 g of 3,4,5-trimethoxphenylacetonitrile in 70 g pyridine was treated with 15 mL 99+% D2O and held at reflux for 24 h.

  All volatiles were stripped first under vacuum and finally with a hard vacuum at room temperature in a Kugelrohr apparatus. The dark residue was treated again with another 30 mL pyridine and another 15 mL 99+%

  D2O. The flask was protected with a drying tube and held at reflux for another 24 h. Again, all volatiles were stripped, and the residue distilled at 110-130 !C at 0.25 mm/Hg to yield 16.77 g of an almost white solid. The GCMS verified this chemical to be 3,4,5-trimethoxy-','-dideuterophenylacetonitrile, with a parent peak at m/e 209 and no visible peak at m/e 207.

  A solution of 250 mL of 1 M LAH in THF was cooled under He to 0 !C and treated with 6.8 mL 100% H2SO4 added very slowly with vigorous stirring. A solution of 18.23 g

  3,4,5-trimethoxy-','-dideuterophenyl-acetonitrile in 200 mL anhydrous THF was added slowly, and following the addition stirring was continued for 20 min. The reaction mixture was brought to a reflux for 30 min on a steam bath, cooled again to 0 !C, and the excess hydride destroyed with 15 mL IPA. About 10 mL of 15% NaOH was required to convert the solids to a filterable white consistency.

  These were removed by filtration, the cake washed with IPA, the filtrates and washes were combined, and the solvent removed under vacuum leaving 17 g of a white oil as residue. This was dissolved in 2 L dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with 3x75 mL CH2Cl2. Removal of the solvent from these extracts under vacuum yielded 10.3 g of a colorless oil which was distilled at 120-130 !C at 0.3 mm/Hg to provide 9.2 g of a white oil. This was dissolved in 50 ml IPA and neutralized with concentrated HCl, producing spontaneous crystals. These were diluted with 50 mL anhydrous Et2O, removed by filtration, washed first with Et2O/IPA, and then with anhydrous Et2O. After air drying, the final yield of 3,4,5-trimethoxy-','-dideuterophenethylamine hydrochloride ('-D) was 10.0 g of white needles.

  DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the hydrochloride salt).

  DURATION: 12 h.

  QUALITATIVE COMMENTS: (with 200 mg) The onset was very gradual and very gentle. At about an hour and a half I was rather out of my body (at least I wasnUt aware of my body, it felt so light). I was listening to Berlioz Requiem, and it took me to the highest realm. I was totally caught up in the magnificence of the music, of the genius it took to compose it, the love it took to complete it, and the devotion of the composer. I felt as though this music had been written for me. What came next is hard to remember because I was so taken with this experience which came only 1 1/2 hours after ingestion. I wondered what time it was and how come I was having a peak experience so soon, because this material was supposed to reach its peak after two hours. Well, now we can revise the records, heh?

  Incidentally this material is really good for interior work. It was a magnificent experience Q one of the best.

  (with 275 mg) I begin to feel it in 15 minutes, stomach getting squeamish. Looking up into the clouds, becoming absorbed in them, watching light grow in intensity, stomach feelings disappeared.

  Became totally absorbed by the music. Listening to Boito's Prologue to Mephistopheles Q exquisitely beautiful, dramatic. Lying on the couch, the music continuing, I was suddenly filled with enormous power. I realized that raw, male power was pouring through me as I had never before experienced it. I was wild, totally self satisfied, and completely oblivious of others and their needs. I wanted to strike out, to win, to conquer. I felt what conquerers have felt in the past, the unbridled passion to vanquish everything. I could see how such misguided power could lead nations to war. Wanting still more power, I was about to find out if God would grant me the power to destroy the world if I wished it, when I felt a gentle kiss on my brow. My wife had leaned over just in time to save the world.

  (with 275 mg) Never had I had such a magnificent appreciation of God.

  It was clear that if I minded my business and turned to Him to learn as I had been doing today, then I could continue to grow and learn in a most wonderful way. It became crystal clear to me that I didnUt have to help anybody or heal anybody, as everyone can turn directly to the source for their needs. An earth-shaking experience.

  (with 300 mg) I had extreme nausea, and vomited. This had a very hard impact on me, and I had to retreat with a paranoia that swept over me without warning. I lay down and let it sweep on, and through this came several very important insights. At least they were important to me. It was about the fourth hour before I could emerge from my retreat, and at that time I knew that I had answered some troublesome personal problems. It was a satisfactory day, but I probably shall not repeat it.

  (with 350 mg) Strong
body awareness started within 15 minutes.

  Visual activity started within half an hour. Visuals were typical kinds, but seemed to arrive earlier. A strong experience of pleasantness started and continued throughout the experience. I tended to internalize to some extent. Ended on a water bed at maybe an hour and a half, pulled covers over me, and went inward with considerable visuals but not much insight. I felt good about where I was. I would not mind being there again, so something was going well.

  I am not sure how long this continued. The visuals decreased somewhere around the 5th or 6th hour. After 8 or 9 hours, activity considerably decreased. I felt quite clear and reasonably centered.

  Would I do this again? The answer is yes.

  (with 500 mg) I consumed the material over a period of twenty minutes, and at the 1 hour 45 minute point, havenUt had any nausea, but I am still careful not to bounce around. Am absolutely grounded even though I am completely into the experience. No more that state in which it is possible to seriously consider trying to rise two inches above the floor and skim, as I do so expertly in dreams. As a matter of fact I havenUt had those dreams for some time now. This material doesnUt allow the straddling of realities as does ordinary mescaline. I know where my realities are, and reality is, basically, where my center is. Thus I am grounded in the physical reality even when the doors are open to non-physical levels.

  EXTENSIONS AND COMMENTARY: The 4-D and the '-D are two of five obvious deuterium isomer derivatives of mescaline. The three remaining are: (1) 3,5-D (4-methoxy-3,5-bis-trideuteromethoxyphenethylamine); (2) 2,6-D (2,6-di-deutero-3,4,5-trimethoxyphenethylamine); and (3) a-D