mL CH2Cl2, washing the extracts with 5% NaOH, and evaporation to yield 5.2 g of an amber oil. The aldehyde, (made from 6.1 g POCl3 and 5.4 g N-methylformanilide, heated until claret colored, then treated with 5.0 g of the above crude thioether, heating for 20 min on the steam bath, into 300 mL H2O, and over-night stirring) was obtained as 3.1 g of a flesh-colored solid that was clearly neither pure nor completely correct. Repeated partitioning with organic solvents and cooling and scratching the residues finally provided a pale orange crystal (1.3 g, mp 88-93 !C) which, after twice recrystallizing from MeOH, gave 0.4 g of pale yellow crystals with a mp 95-96 !C and a textbook perfect NMR
in CDCl3 (CHO, 1H (s) 10.41; ArH 2H (s) 6.93, 7.31; OCH3, 6H, (2s) at 3.88 and 3.92; CH, 1H br. at 3.34; and (CH2)5 10H br. at 1.20-2.34).
The nitrostyrene was prepared from 200 mg of the above aldehyde in 1.2
mL nitroethane and 0.1 g ammonium acetate overnight on the steam bath, the solvent removed to give an orange oil that spontaneously crystallized after a few monthsU standing. This was never characterized, but sits there on the shelf to be reduced to ALEPH-5
some inspired day. The two-carbon homo-logue of this (2,5-dimethoxy-4-cyclohexylthiophenethylamine) will someday be called 2C-T-5 (if it is ever made).
The remaining members of this family, ALEPH-4, ALEPH-6, and ALEPH-7
have actually been prepared and they have all been entered here in Book II, under their own names.
5 ALEPH-4; 2,5-DIMETHOXY-4-(i)-PROPYLTHIOAMPHETAMINE
SYNTHESIS: A solution of 2.0 g
2,5-dimethoxy-4-((i)-propylthio)benzaldehyde (see under 2C-T-4 for its synthesis) in 12 mL nitroethane was treated with 0.4 g anhydrous ammonium acetate and heated on the steam bath for 12 h, then allowed to stir for another 12 h at room temperature. The excess solvent/reagent was removed under vacuum leaving a residue as a heavy deep orange two-phase oily mass. This was brought into one phase with 2 mL MeOH and then, with continued stirring, everything spontaneously crystallized. This product was removed by filtration and, after washing sparingly with cold MeOH and air drying, yielded 2.0 g of 1-(2,5-dimethoxy-4-(i)-propylthiophenyl)-2-nitropropene as orange crystals with a mp of 96-98 !C. After recrystallization from 15 mL
boiling 95% EtOH, filtering and air drying to constant weight, there was obtained 1.6 g of orange crystals with a mp of 99-100 !C.
A suspension of 1.0 g LAH in 100 mL warm THF was stirred under a N2
atmosphere and heated to a gentle reflux. To this there was added, dropwise, a solution of 1.2 g
1-(2,5-dimethoxy-4-(i)-propylthiophenyl)-2-nitropropene in 20 mL
anhydrous THF. This mixture was held at reflux for 1 day, then stirred at room temperature for 2 days. There was then added, slowly and with caution, 1 mL of H2O, followed by 1 mL of 15% NaOH, and finally by another 3 mL of H2O. Stirring was continued until the reaction mixture became white and granular, then all solids were removed by filtration and the filter cake was washed with additional THF. The filtrate and washings were combined, and the solvent removed under vacuum to give 1.1 g of residue which was an almost white oil.
This was dissolved in 6 mL IPA, neutralized with concentrated HCl (10
drops were required) and then diluted with 200 mL anhydrous Et2O. The resulting slightly turbid solution was clarified by filtration through a sintered glass filter, and the clear and slightly yellow filtrate was allowed to stand. A fine white crystalline product slowly separated over the next few h. This product, 2,5-dimethoxy-4-(i)-propylthioamphetamine hydrochloride (ALEPH-4) was removed by filtration, and after washing with Et2O and air drying, weighed 0.5 g and had a mp of 146-147 !C, with prior sintering at 144
!C.
DOSAGE: 7 - 12 mg.
DURATION: 12 - 20 h
QUALITATIVE COMMENTS: (with 7 mg) Things started off going downhill, initially negative with tension and depression, but as the momentum developed, so did the positive effect. My discomfort continued to develop, but I was struck by the visual beauty of the trees and the small stream that flowed off the mountain. My experience continued to grow, simultaneously, in both the negative and the positive direction.
Physically I was uncomfortable and found my breathing difficult, but I acknowledged a rapture in the very act of breathing. All moved over to the plus side with time, and the evening was gorgeous. I have never seen the sky so beautiful. The only flaw was when I choked on some lemonade and it seemed to me I almost drowned. I have been extremely conscious of eating, drinking and swallowing ever since. I barely slept the whole night and awoke extremely tired. I felt that the experience continued for many days, and I feel that it is one of the most profound and deep learning experiences I have had. I will try it again, but will block out more time for it.
(with 8 mg) There was without question a plus two, but none of the edges of unreality that are part of LSD. The sounds that are just outside of my hearing are intriguing, and distract me from the eyes-closed imagery that is just barely possible with music while lying down. But, going outside, there were no obvious sources of the sounds that I heard. Could I drive? I suspect so. I took a shower and did just that Q I drove to San Francisco without incident, and walked amongst the many strange faces on the downtown streets.
(with 12 mg) The experience was very intense but completely under control except for a twenty minute period right in the middle of it.
I had to get away from everything, from everyone. There was a sense of being surrounded and moved in upon that was suffocating. I was weighed down with everything Q physical, psychic, emotional. My clothes had to come off, my hair had to be released, my shoes went, I needed to move away from where I was, to somewhere else, to some new place, any new place, with the hope that my other old place wouldnUt follow me. Pretty soon I found I was myself, I could breathe again, and I was OK. Rather sheepishly, I dressed and rejoined the group.
The rest of the day was spectacular, but those few minutes were scary.
What if I couldnUt have escaped?S
EXTENSIONS AND COMMENTARY: Again, there are hints and suggestions of complexities. These, and several other reports, suggest some sensory confusion, and interpretive aspects that are to some extent threatening. There is an underlying suggestion of body toxicity. I know of no experiment that exceeded 12 milligrams and I would not be able to predict what might come forth at higher dosages. I personally choose not to try them.
6 ALEPH-6 2,5-DIMETHOXY-4-PHENYLTHIOAMPHETAMINE
SYNTHESIS: To a 300 mL three-neck round-bottom flask set up with a magnetic stirrer and protected with a N2 atmosphere, there was added 75 mL hexane, 3.5 g tetramethylethylenediamine, and 4.2 g p-dimethoxybenzene. The reaction mixture was cooled to 0 !C with an external ice bath, and there was then added 19 mL of 1.6 M
butyllithium in hexane. With stirring, the reaction was brought up to room temperature, and there were produced loose, creamy solids. There was then added, as a solid and portionwise, 6.6 g diphenyldisulfide which resulted in an exothermic reaction and the production of a nearly clear solution. After stirring an additional 10 min, the reaction was quenched in 500 mL of dilute NaOH. The hexane phase was separated, and the aqueous phase extracted with 4x100 mL CH2Cl2 The organic extracts were combined, washed with dilute HCl and the solvents were removed under vacuum to provide 6.0 g of 2,5-dimethoxyphenyl phenyl sulfide as an impure amber oil. A small sample was saved for microanalysis and NMR, and the re-mainder converted to the corresponding benzaldehyde.
A mixture of 6.1 g POCl3 and 5.4 g N-methylformanilide was heated for 3 min on the steam bath, and then added to the remainder of the above-described 2,5-dimethoxyphenyl phenyl sulfide. The reaction became immediately a deep red and, after heating on the steam bath for 0.5 h, was dumped into a large quantity of H2O, producing a granular brown solid. This was removed by filtration, and washed sparingly with cold MeOH (the washes were saved). The resulting pale yellow solids were recrystallized from 20 mL boiling absolute EtOH providing, after cooling, filtration and air drying, 4.4 g of extremely pale yell
ow crystals of 2,5-dimethoxy-4-(phenylthio)benzaldehyde. This had a mp of 119-119.5 !C. All washes and mother liquors were combined, flooded with H2O and extracted with CH2Cl2. This solvent was removed under vacuum, and the residue (a viscous oil) was dissolved in a little EtOH which, on cooling in dry ice, gave 1.2 g of a second crop of the aldehyde, mp 117-119 !C. Recrystallization from 5 mL 95% EtOH
gave an additional 0.4 g product with a mp of 118-119 !C. This mp was not improved by recry-stallization from cyclohexane. The NMR specrum was excellent, with OCH3 singlets (3H) at 3.45 and 3.80 ppm; ArH
singlets at 6.28 and 7.26 ppm, the C6H5 as a broad peak centered at 7.50, and the CHO proton at 10.37 ppm.
A solution of 4.4 g 2,5-dimethoxy-4-(phenylthio)benzaldehyde in 32 mL
nitroethane was treated with 0.8 g anhydrous ammonium acetate and heated on the steam bath for 21 h. The excess solvent/reagent was removed under vacuum, leaving a dark red oil as residue. After much diddling and fiddling around, this set up as a crystalline mass.
These solids were ground under 20 mL cold MeOH and filtered, providing 5.3 g of the crude nitrostyrene as an orange crystalline residue product after air-drying. This was ground up under 10 mL MeOH, the insolubles collected by filtration, washed with a little MeOH, and air dried to provide 5.3 g crude
1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene as yellow crystals, with a mp of 100-102 !C (with prior sintering at about 98
!C). This was recrystallized from 50 mL boiling 95% EtOH. After cooling in an ice bath, it was filtered, washed with EtOH, and air drying provided gold-yellow crystals with a mp of 105-106 !C. The proton NMR was excellent (in CDCl3).
A suspension of 2.0 g LAH in 100 mL refluxing THF, under an inert atmosphere and with good stirring, was treated with a solution of 3.5
g 1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene in 20 mL
anhydrous THF added dropwise at a rate that maintained the reflux.
Heating and stirring were maintained for an additional 36 h, and then the reaction mixture was stirred at room temperature for an additional 24 h. There was added 2.0 mL H2O (dissolved in a little THF), followed by 2.0 mL 15% NaOH, and finally another 6.0 mL H2O. Stirring was continued until all formed 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 2.8 g of an oil that quite obviously contained some H2O. This was dissolved in 400 mL CH2Cl2, washed first with dilute NaOH and then with 4x150 mL 1N HCl. The organic phase was stripped of solvent under vacuum, yielding a pale amber oil that crystallized. This was ground first under Et2O, giving 3.4 g of a yellow solid. This was then ground under 10 mL of acetone, yielding 2.4 g of a white crystalline solid that darkened at 170 !C, sintered at 187 !C and had a mp of 191-193 !C. This was dissolved in 20 mL hot 95% EtOH, and diluted with 40 mL Et2O to provide a clear solution which, after a minute's scratching with a glass rod, deposited 2,5-dimethoxy-4-phenylthioamphetamine hydrochloride (ALEPH-6) as white solids. After filtration and air drying, the weight was 1.8 g, with a mp of 194-195 !C. The dilute HCl washes, after being made basic with aqueous NaOH and extraction with CH2Cl2 gave a trivial quantity of additional product.
DOSAGE: greater than 40 mg.
DURATION: probably long.
QUALITATIVE COMMENTS: (with 30 mg) I had an alert at the one hour point, and in another hour there was a clear 1+. There was a not well defined, gentle un-worldliness. And it was still there quite unchanged twelve hours later. In a group I find that all voices about me are of equal intensity and equal importance. But this is not at all distracting. This will be a long lived thing for sure.
(with 40 mg) I am into a subtle but real effect, no more than one plus, but real. I feel primed, but nothing more. It is not interfering with work, maybe even helping with it. After another hour of static one-plusness I decided to use it as a primer to LSD, using the usual 60 microgram quantity that is standard for primer studies.
The combination showed definite synergism, with a rapid show of the LSD effects (within fifteen minutes) and an almost three plus effect.
This is most unusual for the usual 60 microgram challenge amount. An absolutely delightful intoxication that had sufficiently descended towards baseline that I accepted a ride to a party that evening in Marin County to attend a poetry reading. There I felt myself at baseline and accepted (unusual for me) a little marijuana. And with the utmost quiet and delicacy, a rather incredible change of state took place. The most memorable event was the awareness of a clarinet playing somewhere, and the sneaky sounds from it actually coming along the carpet out of the dining room and into the hallway and through the door and into the room where I was, and all of them gathering at my feet like docile kittens waiting for me to acknowledge them. I did, non-verbally, and I was amazed at the many additional follow-up sounds that came from the same clarinet along the same twisty path along the floor and through the door and into my space, over what seemed to be the next million hours. I ended up with a marvelous collection of notes and phrases at my feet, and I felt somehow honored. My speech sounded OK to me, but I knew that it would be odd to the ears of others, so I kept quiet. A final measure of the weirdness of the ALEPH-6/LSD/Pot combination was the viewing of the Larkspur ferry at its dock, abandoned for the evening and with no one aboard it, and with all that clean, dry sleeping space going to waste with so many people sleeping on the streets these days. Once home, I slept soundly and for a long while. Incredible experience.
EXTENSIONS AND COMMENTARY: In a sense, this compound was a disappointment. The beauty of putting a whole new ring into an active structure is that it provides a marvelous vehicle for introducing new substituents in new arrangements. Had Aleph-6 been a cleanly active and potent compound, then the new phenyl group could have been made electronegative to varying degrees (with methoxy substitution for example) or electropositive to varying degrees (with trifluoromethyls or nitros) and this fine-tuning could have been extremely rewarding.
But this material had the earmarks of one of those forever threshold things. The 40 milligram experiment was hopelessly compromised, and nothing higher was ever scheduled or tried. The two-carbon homologue, 2,5-dimethoxy-4-phenylthiophenethylamine, or 2C-T-6, has never even been synthesized, let alone assayed.
7 ALEPH-7; 2,5-DIMETHOXY-4-(n)-PROPYLTHIOAMPHETAMINE
SYNTHESIS: A solution of 2.6 g
2,5-dimethoxy-4-((n)-propylthio)benzaldehyde (see under 2C-T-7 for its synthesis) in 20 mL nitroethane and 0.5 g anhydrous ammonium acetate was heated on the steam bath overnight. The excess solvent/reagent was removed under vacuum leaving an orange oil as a residue that cry-stallized spontaneously. This crude product was recrystallized from 20 mL boiling MeOH to give, after cooling, filtering, and air drying, 2.4 g of
1-(2,5-dimethoxy-4-(n)-propylthiophenyl)-2-nitropropene as orange crystals. Its mp was 83-84 !C with prior sintering at 81 !C.
A suspension of 1.5 g LAH in 150 mL of warm anhydrous THF was stirred under an inert atmosphere and brought up to a gentle reflux. A solution of 2.3 g
1-(2,5-dimethoxy-4-(n)-propylthiophenyl)-2-nitropropene in 25 mL
anhydrous THF was added dropwise at a rate that maintained the reflux.
Heating and stirring were continued for 2 days, and then the reaction mixture was allowed to stir at room temperature for an additional 2
days. There was added 1.5 mL H2O (dissolved in 10 mL THF), followed by 1.5 mL 15% NaOH, and finally another 4.5 mL H2O. Stirring was continued until all the curdy solids had turned white. The reaction mixture was filtered, and the filter cake washed with slightly wet THF. The filtrate and the washings were combined, and the solvent removed under vacuum. The residue was about 2 mL of an amber colored oil that was dissolved in 200 mL CH2Cl2. This solution was washed with first dilute NaOH, and then with saturated brine. Removal of the solvent gave a pale amber oil that was dissolved in 10 mL IPA, neutralized with about 14 drops of concentrated HCl, and diluted with 2
00 mL anhydrous Et2O. The clear solution was decanted from a little gritty material, and then set aside to allow the formation of 2,5-dimethoxy-4-(n)-propylthioamphetamine hydrochloride (ALEPH-7) as fine white crystals. After filtration and air drying, there was obtained 1.8 g of an off-white powder.
DOSAGE: 4 - 7 mg.
DURATION: 15 - 30 h.
QUALITATIVE COMMENTS: (with 4 mg) At the second hour I had a paraesthetic twinge or two (all pins and needles), and then felt quite relaxed, quite willing to let this play itself out. In the evening my ears still feel 'popped' and there is a little bit of physical awareness. There is not much fun with this. The night following, I was unable to sleep and only dozed slightly, but I seemed to be OK the next day.
(with 6 mg) The alert was felt within a half hour, and then nothing more. Then, over the next two hours, there was the evolution of an extremely neutral state. I danced wildly to a record of Keith Jarrett, but somehow didnUt care for his style. I fell apart emotionally, with tears and a feeling of total loss of everything.
Everything was visible to me only in some strange wide-angle lens viewing. I went for a walk, a waste of time. I tried classical music, but only jazz was acceptable. It was a couple of days before I lost the residual strangeness feeling. Never again.
(with 7 mg) I did this alone, and in retrospect I wish I had not.
Somewhere between the hours 2 and 3, I got to a full +++, and I was concerned that I saw the effects still developing. Where would it go now? There was no reality loss as with LSD, no shakes or shimmers, but an intense and profound +++ of something characterized only by the absence of extremes. And I am frightened because this is still deepening. A couple of calls to friends were not successful, but I found an ally in the Palo Alto area, and I told him I was coming to visit. My greater than one hour drive there was okay only because I had programmed every move ahead of time. In retrospect, to drive was completely stupid, and I certainly will never do it again, under any circumstances. But, there I was. I knew which lane I would be on, on the S.F. Bay Bridge, at every moment of my travels. The middle lane through the tunnel. The second from the left when descending into San Francisco. The white lane-marker stripes were zipping up past my lateral field of vision as I drove, those that were to my right zipped past my right eye, those to the left past my left eye. Like disturbed fruit flies leaving an over-ripe peach. But, as everything had been preprogrammed, there were no surprises. I made it successfully, and my baby-sitting friend probed, with a blend of curiosity, love, and envy, my uncaring state. And in the course of the next couple of hours, this state evolved into a friendly, familiar place. I was still fully +++, but now for the first time I was at peace with it. A fruit salad tasted heavenly. By midnight I was able to doze lightly, and the next day I was sure that there were some residual effects.
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