Pihkal
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(C13H15NO3S) C,H.
A suspension of 4.0 g LAH in 150 mL anhydrous THF under N2 was cooled to 0 !C and vigorously stirred. There was added, dropwise, 2.8 mL
100% H2SO4, followed by 5.5 g
3,5-dimethoxy-4-allyloxyphenylacetonitrile in 10 mL anhydrous THF.
The reaction mixture was stirred at 0 !C for a few min, then brought to a reflux on the steam bath for 30 min. After cooling back to room temperature, there was added sufficient IPA to destroy the excess hydride, followed by sufficient 10% NaOH to form granular solids.
These were removed by filtration, and washed with 20 mL IPA. The filtrate and washes were stripped of solvent under vacuum andthe residue added to 100 mL dilute H2SO4. This was washed with 2x50 mL
CH2Cl2, made basic with aqueous NaOH, and extracted with 2x75 mL
CH2Cl2. These extracts were pooled, the solvent removed under vacuum, and the residue distilled at 110-120 !C at 0.4 mm/Hg to give 4.9 g of a colorless oil. This was dissolved in 15 mL IPA, neutralized with concentrated HCl (55 drops required), and diluted with 50 mL Et2O.
The product was removed by filtration, washed with Et2O, and air dried to give 4.9 g of 3,5-dimethoxy-4-allyloxyphenethylamine hydrochloride (AL) as white crystals.
DOSAGE: 20 - 35 mg.
DURATION: 8 - 12 h.
QUALITATIVE COMMENTS: (with 24 mg) I first became aware of something in about 10 minutes, a pleasant increase in energy. By 20 minutes it was getting pronounced and was a nice, smooth development. During the next hour positive and negative feelings developed simultaneously.
Following a suggestion, I ate a bit of food even though I had not been hungry, and to my surprise all the negative feelings dropped away. I felt free to join the others wherever they were at. I moved into the creative, free-flowing kind of repertoire which I dearly love, and found everything enormously funny. Much of the laughter was so deep that I felt it working through buried depressions inside me and freeing me. From this point on, the experience was most enjoyable.
The experience was characterized by clear-headedness and an abundance of energy which kept on throughout the day and evening. At one point I went out back and strolled along to find a place to worship. I had a profound sense of the Presence and great love and gratitude for the place, the people, and the activities taking place. The come-down from the experience was very gradual and smooth. Food tasted wonderful. I went to bed late, and quite ready for bed, although the energy was still running. However, sleep was not long in coming.
(with 24 mg) The onset was extremely gradual and graceful, with the first alert that one could really sense at about 50 minutes. This was succeeded by a slow gentle climb to the peak at one hour and fifteen minutes. The experience itself left all of the sensory modalities functional; speech was cogent and rather fluid. In fact, there was an unusual ease of free association. All throughout the session, the talk was high in spirits and somehow indicative of an inner excitement. Affect was entirely pleasant, but not exalting nor conducive to insight or to problem solving. There were no requirements for withdrawal into the self. The material seemed wholly social in nature. No visual, auditory or olfactory sharpening was in evidence. The plateau for this material seemed unusually long. I was unable to sleep for several hours, and took 25 mg Librium before sleep arrived. The next day was a lethargic and slow one, with the inner feeling that the effects had not worn off until the middle of the day following ingestion.
(with 35 mg) I was a distinct +1 in 35 minutes and a +2 by the end of the hour. My head congestion in no way cleared up, absolving the material from having that particular virtue. The entire experience was somewhat dissociated Q I could not connect with my feelings.
Although my mind remained clear, there was a hangover feeling at the end of the experiment.
EXTENSIONS AND COMMENTARY: This compound was first explored in Prague by Leminger. He provided only the synthetic details and the statement that it was the most active compound that he had studied, with activity at 20 milligrams, with perceptual changes, color enhancement, and difficult dreams during sleep that night. Some effects persisted for more than 12 hours. Dosages above 35 milligrams remain unexplored.
As AL is one of the most potent 3,4,5-trisubstituted phenethylamines yet described, and since the corresponding amphetamines are of yet greater potency, it would be a good guess that 4-allyloxy-3,5-dimethoxyamphetamine (3C-AL) would be an interesting compound to explore. It could be made from syringaldehyde in reaction with allyl iodide, followed by the formation of a nitrostyrene with nitroethane, followed by reduction with aluminum hydride. It is, as of the present time, both unsynthesized and unexplored.
3 ALEPH; DOT; PARA-DOT; 2,5-DIMETHOXY-4-METHYLTHIOAMPHETAMINE
SYNTHESIS: A solution of 2.3 g
2,5-dimethoxy-4-(methylthio)benzaldehyde (see under 2C-T for its synthesis) in 7.5 mL nitroethane was treated with 0.45 g anhydrous ammonium acetate and heated on the steam bath for 6 h. The excess solvent/reagent was removed under vacuum leaving a mass of orange crystals as residue. These were ground up under 10 mL MeOH, col-lected by filtration, washed with a little MeOH, and air dried to provide 2.6 g crude
1-(2,5-dimethoxy-4-methylthiophenyl)-2-nitropropene. After recrystallization from 140 mL boiling MeOH, filtering and drying there was in hand 1.8 g of bright orange crystals with a mp of 137-138 !C.
Anal. (C12H15NO4S) C,H,N,S.
A suspension of 1.4 g LAH in 10 mL anhydrous Et2O and 40 mL anhydrous THF was put under an inert atmosphere and, with good stirring, brought up to a gentle reflux. A solution of 1.8 g 1-(2,5-dimethoxy-4-methylthiophenyl)-2-nitropropene in 30 mL anhydrous THF was added dropwise at a rate that maintained the reflux. Heating and stirring were maintained for an additional 7 h, then the reaction mixture was allowed to return to room temperature. There was added 1.6 mL H2O (dissolved in a little THF), followed by 1.6 mL 15% NaOH, and finally another 4.8 mL H2O. Stirring was continued until all the curdy solids had turned white. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate and the washings were combined, and the solvent removed under vacuum. The residue was 1.3 g of a colorless oil that solidified. Its mp of 90-93 !C was improved slightly to 91-93 !C with recrystallization from hexane. The product was dissolved in 25 mL warm IPA, neutralized with concentrated HCl (0.57 mL required) and then diluted with 100 mL anhydrous Et2O. After a moment's delay, the white crystalline product appeared. It was removed by filtration, washed with Et2O, and air dried to provide 1.2
g 2,5-dimethoxy-4-methylthioamphetamine hydrochloride (ALEPH) with a mp of 200-201 !C. Recrystallization from IPA gave an analytical sample with a mp of 204-205 !C. Anal. (C12H20ClNO2S) C,H; N: calcd, 5.04; found, 5.52.
DOSAGE: 5 - 10 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 5 mg) The initial hints of action were physical Q warming of first the legs, and then a comfortable warmth spread over the entire body. Intense intellectual stimulation, one that inspired the scribbling of some 14 pages of handwritten notes.
Which is a pretty good record for an experience that is almost entirely non-verbal. The afterglow was benign and rich in empathy for everything. And by the sixth hour I was quite hungry.
(with 10 mg) There was a rapid shift of frame of reference that made simple tasks such as reading and tuning the radio quite alien. I happened to catch the eyes of Pretty Baby, the cat, at the same moment she looked at me, and she turned and fled. I am able to interact with people on the telephone quite well but mechanical things, such as arranging flowers or alphabetizing names, are beyond me. Driving would be impossible.
EXTENSIONS AND COMMENTARY: This specific compound is probably the first sulfur-containing phenethylamine to have been evaluated as a potentially active CNS stimulant or psychedelic. It was a complete, total, absolute unknown. The first trials were made at the sub-microgram level, specifically at 0.25 micrograms, at 11:30 AM on September 3, 1975. Part of this extreme precaution was due to the uniqueness of a new heteroatom in a phen
ethylamine system. But part was due to the strange manic excitement that occurred at the time of the isolation and characterizing of the final product in the laboratory. Although it was certainly all placebo response, I was jumpy and unable to stay in the lab for more than a few minutes at a time. Maybe dust in the air? Maybe some skin contact with the free base? Now, I know there was nothing, but the possibility of extraordinary potency was real, and I did indeed wash everything down anyway. In fact, it took a total of 18 trials to work the experimental dosage up to as much as a single milligram. In retrospect, overly cautious. But retrospection, as they say, is cheap.
The 5 milligram experiment, briefly quoted from above, is the stuff of Chapter 14 of this book, important in that it gives an interesting example of some thought processes associated with psychedelic intoxication, ego-inflation, and what might be thought of as bits of mania. As is always the case with peak experiences that happen to be catalyzed by drugs, this extraordinary event could not be duplicated.
At 7 milligrams there was an uneventful +1, and some 10 milligrams was needed to generate a full +3 experience. The first clue of the erratic nature of the Aleph family came from an independent assay by a colleague of mine, one who was very familiar with such states of consciousness, but for whom this was not a time for peak experiences.
At 10 milligrams he told me that he had had only mild effects which he found relatively uninteresting.
As it stands, ALEPH remains relatively unexplored. Its two positional isomers are entered here as ORTHO-DOT and META-DOT. Three higher homologues have been more thoroughly looked at, and the generic name ALEPH (the first letter of the Hebrew alphabet) was given this group on the basis that they might have extraordinary properties in common.
But the real treasure came in the exploring of the 2-carbon homologues, the compounds that make up the 2C-T family. Here, there proved to be much less uncertainty as to reasonable dosages, and much more richness in the subjective nature of the experience.
4 ALEPH-2; 2,5-DIMETHOXY-4-ETHYLTHIOAMPHETAMINE
SYNTHESIS: A solution of 2.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde (see under 2C-T-2 for its synthesis) in 12 mL nitroethane was treated with 0.4 g anhydrous ammonium acetate and heated on the steam bath for 3 h. All volatiles were removed under vacuum, leaving a residue that set up as brilliant red crystals. These were mechanically removed from the evaporation flask, blown free of nitroethane vapor, and recrystallized from boiling EtOH, producing 1.8 g pale orange crystals, with a mp of 110-112 !C. Recrystallization from 20 mL
boiling IPA gave, after filtering and air drying, 1.70 g light orange crystals of 1-(2,5-dimethoxy-4-ethylthiophenyl)-2-nitropropene with a mp of 112-113 !C.
A suspension of 1.2 g LAH in 75 mL anhydrous THF was put under an inert atmosphere and, with good stirring, brought up to a gentle reflux. A solution of 1.5 g
1-(2,5-dimethoxy-4-ethylthiophenyl)-2-nitropropene in 20 mL anhydrous THF was added dropwise. Heating and stirring were maintained for an additional 24 h, and then the reaction mixture was allowed to come back to room temperature with stirring. There was added 1.4 mL H2O
(dissolved in a little THF), followed by 1.4 mL 15% NaOH and finally another 4.2 mL H2O. Stirring was continued until all the curdy solids had turned white. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate and the washings were combined, and the solvent removed under vacuum. The residue was 1.1 g of a pale amber oil. This was dissolved in 6 mL IPA, neutralized with concentrated HCl (about 8 drops were required) and then diluted with 150 mL anhydrous Et2O. The slightly cloudy solution was stirred for a couple of min, then there was the formation of a heavy white crystalline mass. This was removed by filtration, washed with Et2O, and air dried to provide 1.1 g 2,5-dimethoxy-4-ethylthioamphetamine hydrochloride (ALEPH-2) with a mp of 128-130 !C with decomposition.
DOSAGE: 4 - 8 mg
DURATION: 8 - 16 h.
QUALITATIVE COMMENTS: (with 4 mg) There was a warm feeling in the total body and a light pressure in the head that changed with time into the feeling of a balloon without any anatomical definition. The usual color perception was not very much increased, and my vision was not sharpened as it was with DOM. Rather, I noticed waves of movement, very smooth and not too busy. Both my tactile perception and auditory acuity were enhanced. The main effect for me was, paradoxically, an easier handling of the outer world. None of the jitters of amphetamine. The body feeling is good, healthy, and I am at peace with the body-mind dualism. These are pretty much personal comments Q I will write up the pharmacological points later.
(with 5 mg) This turned out to be a day of extraordinary visuals and interpretations. About two hours into it, I felt that the effects were still climbing, but there was a marvelous onset of visual distortions and illusions, right at the edge of hallucination. The logs in the fireplace were in continuous motion. The notepaper I was writing on seemed to scrunch and deform under the pressure of the pen.
Nothing would stay still; everything was always moving. There was a phase of unabated inflation. The intensity was noticeably dropping at the five hour point and I observed considerable residual shakes and a muscular tremor. Even towards midnight there was some tooth-rubbiness, but I was able to get a somewhat fretful though adequate sleep.
(with 5 mg) I was exposed to a number of new environments and it was difficult to completely separate the experience into what was seen differently and what was seen for the first time. The Santa Cruz Mystery Spot should have been bizarre but it was simply hokey. And yet the boardwalk that should have been depressing was totally magical. The day was unworldly and I ended up with considerable muscular weakness. All in all, I handled it well, but I probably wonUt do it again.
(with 7 mg) An amazing unification of visual hallucination seen only in the very fine detail of something, and what must be considered retinal hallucination. There is no one-to-one correspondence between the many retinal cells of the high-resolution part of the eye. Thus, the mind can pick and choose, sometimes from the right eye, and sometimes from the left. And so a small curve or bump can become whatever you wish. For a moment. And then it chooses again, but differently. Is all of our perceived world as subjective as this?S
(with 8 mg) Extreme intoxication, but almost no visual phenomena.
Even well into the evening, I know I absolutely could not drive. Why?
I donUt know, since this experiment, at least, seemed to be quite free of strange colors and wiggly lines and streaks of light. It's that I donUt trust that the reality I see is the same reality that the other driver might see. I am very much the center of the world about me, and I donUt think I could trust anyone else to fully respect my reality.
EXTENSIONS AND COMMENTARY: As with ALEPH itself, and in most ways with the entire ALEPH family, there is no predictability of the dose/response relationship. One person had expressed his psychic isolation by taking and maintaining a fetal position in relative hibernation for several hours and with substantial amnesia; this at a four milligram dose. Yet another person, at fully twice this amount, was aware of a slight light-headedness that could in no way be measured as more than a bare threshold. But by the time this erratic nature had become apparent, the ALEPHS had been assigned and made, up to and including ALEPH-7.
ALEPH-3 was intended to be the methallylthio compound, 2,5-dimethoxy-4-('-methallylthio)amphetamine. The thioether (2,5-dimethoxyphenyl '-methallyl sulfide) was easily made from 2,5-dimethoxythiophenol (see 2C-T-2 for its preparation) with 3.4 g dissolved in a solution of 1.7 g KOH in 25 mL boiling EtOH, and 2.72 g methallyl chloride, heated 1 h on the steam bath, poured into 250 mL
H2O, extracted with 3x100 mL CH2Cl2, and solvent removal yielding 4.4
g of the sulfide as an amber oil. An effort to convert this to 2,5-dimethoxy-4-('-methallylthio)benzaldehyde (7.2 g POCl3, 6.7 g N-methylformanilide, 4.2 g of the crude sulfide from above, 15 min heating on the steam bath, H2O hydrolysis, hexane extraction of the residues from a CH2Cl2 extraction) produced 3.1 g of a pe
ppermint-smelling oil that distilled at 140-160 !C at 0.3 mm/Hg and which did indeed have an aldehyde group present (by proton NMR) but the rest of the spectrum was a mess, and the project was abandoned.
Several years later, this entire project was reinitiated, and the aldehyde was obtained as a yellow crystal, but again it was not pursued. At that time, the earlier try had been totally forgotten, and a brand new ALEPH- (or 2C-T-) number had been assigned; i.e., 20.
Thus, the corresponding phenethylamine (2,5-dimethoxy-4-('-methallylthio)phenethylamine), had it ever been made, which it was not, would have been called either 2C-T-3 or 2C-T-20, and the amphetamine homologue would probably have been ALEPH-20.
A closely related 2C-T-X compound was also started quite a while later Q this was the allylthio homologue of the methallyl material 2C-T-3 or 2C-T-20. Its place in the flow of things is evident from its numbering, 2C-T-16. A mixture of 2,5-dimethoxythiophenol and KOH and allyl chloride in MeOH gave 2,5-dimethoxyphenyl allyl sulfide as a white oil which boiled at 110-125 !C at 0.25 mm/Hg. This, with POCl3
and N-methylformanilide provided
2,5-dimethoxy-4-(allylthio)benzaldehyde which distilled at 140-160 !C
at 0.4 mm/Hg and could be recrystallized from MeOH as a pale yellow solid. Reaction of this aldehyde in nitroethane in the presence of ammonium acetate (steam bath for 2.5 h) provided 2,5-dimethoxy-4-allylthio-'-nitrostyrene as red crystals from acetonitrile. Its mp was 114-115 !C. Anal. (C13H15NO4S) C,H. This has not yet been reduced to the final amine, 2,5-dimethoxy-4-allylthiophenethylamine, 2C-T-16. The corresponding amphetamine would be, of course, ALEPH-16.
ALEPH-5 was to be the cyclohexylthio analogue (2,5-dimethoxy-4-cyclohexylthioamphetamine). The thioether (2,5-dimethoxyphenyl cyclohexyl sulfide) was successfully made from 1.7 g 85% KOH pellets in 25 mL hot EtOH, 3.4 g 2,5-dimethoxythiophenol (again, see under 2C-T-2 for its preparation), and 4.9 g cyclohexyl bromide, 3 h on the steam bath, into 500 mL H2O, extraction with 3x100