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From: sender@mit.edu Newsgroups: sci.med,sci.chem,alt.drugs Subject: PiHKAL: The Chemical Story. File 3 of 6 (I'm posting this for a friend.) This is part 3 of 6 of the second half of PiHKAL: A Chemical Love Story, by Alexander Shulgin and Ann Shulgin. Please forgive any typos or misprints in this file; further, because of ASCII limitations, many of the typographical symbols in the original book could not be properly represented in these files. If you are seriously interested in the chemistry contained in these files, you should order a copy of the book PiHKAL. The book may be purchased for $22.95 ($18.95 + $4.00 postage and handling) from Transform Press, Box 13675, Berkeley, CA 94701. California residents please add $1.38 State sales tax. At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.... No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herin, without being familiar with that drug's action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law. #60 DMPEA; 3,4-DIMETHOXYPHENETHYLAMINE SYNTHESIS: A solution of 33 g 3,4-dimethoxybenzaldehyde in 140 mL acetic acid was treated with 23 mL nitromethane and 12.5 g anhydrous ammonium acetate, and heated on the steam bath for 45 min. To this there was slowly added, with good stirring, 300 mL H2O, and the resulting solids were removed by filtration. The product was finely ground under a small amount of MeOH, filtered again, and air dried to give 13.5 g 3,4-dimethoxy-'-nitrostyrene with a mp of 142-143 !C. To a stirred suspension of 12.0 g LAH in 500 mL anhydrous Et2O that was at a gentle reflux and under an inert atmosphere, there was added 11.45 g 3,4-dimethoxy-'-nitrostyrene by leaching it from a thimble in a modified Soxhlet condenser. The addition took 2 h and the refluxing was maintained for another 16 h. After cool-ing to room temperature, the excess hydride was destroyed by the cautious addition of 500 mL 1.5 N H2SO4. The phases were separated, and to the aqueous phase there was added 250 g potassium sodium tartrate. The pH was brought to >9, and the clear solution was extracted with 3x100 mL CH2Cl2. Remo-val of the solvent from the combined extracts under vacuum gave 5.2 g of a pale yellow oil. This was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas, giving 5.0 g of a slightly sticky off-white solid. This was recrystallized from 75 mL of boiling CH3CN to give 3.3 g 3,4-dimethoxyphenethylamine hydrochloride (DMPEA) as beautiful white crystals. DOSAGE: greater than 1000 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 500 mg) Nothing. (with 1000 mg) Nothing. (with 10 mg i.v.) RNothing. (with 1000 mg of 3,4-dimethoxyphenylacetic acid, a major human metabolite of DMPEA) RNothing. (with 500 mg of N-acetyl-3,4-dimethoxyphenethylamine, a major human metabolite of DMPEA) RNothing. EXTENSIONS AND COMMENTARY: Why all the interest? Why keep pursuing a compound that is so obviously without activity? Or a metabolite that is also without activity? The answer is that these are totally fascinating compounds just because they have no activity! By the way, in this instance, I actually made up most of the quotations. I am not sure that the subjects actually said, RNothing,S but they did report that there were no effects. In my own experiments, my notes record the phrase, RNo effects whatsoever. A little background: one of the transmitter heavyweights in the brain is dopamine. Dopamine is called dopamine because it is an amine that comes from an amino acid that is 3,4-dihydroxyphenylalanine and this, in German, is Di-Oxo-Phenyl-Alanine, or DOPA. The levo-optical (or L-) isomer of DOPA has rather cutely been called the punch-drunk Spanish matador, or El Dopa. But that is not part of the story. The story is really about the RPink Spot of Schizophrenia.S Many years ago, an observation was made in a biochemical laboratory on the East Coast that stirred up a rolling controversy. It had been found that if the urines of schizophrenic patients (sloppily called Rschizophrenic urinesS) were extracted in such and such a way, and the extracts chromatographed, a pink spot would develop at a particular place on the chromatogram. Well, if this proved to be true with urines of a sick population, and were this proved to be different from the urines of a healthy population, it would constitute an objective diagnosis of schizophrenia. A simple chemical test to confirm a pathology that had defied all efforts to achieve consensus amongst the psychiatrists of the world. The literature was suddenly filled with dozens of papers. Researcher A confirmed that the pink spot was found with schizophrenics, and not with normal controls. Researcher B found the pink spot in all urines, regardless of pathology. Researcher C found it in no urines at all. Researcher D argued that it was a factor from the hospital diet. Researcher E found that the pink spot reflected the time of day that the urine sample was collected. Researcher F drew a conclusion about where truth might lie by tallying the number of papers that supported argument A, B, C, D, or E. The only confirmable fact that endured was that the pink spot was due to DMPEA. So a bright spotlight was directed towards its possible role in mental illness. And this expressed itself in the simple question: would it produce schizophrenia in a normal subject? No. And in a way I am comforted that that did not evolve into a simple litmus test for a schizophrenic diagnosis. There are so many cultural, political, and social factors that come to bear on the assignment of a diagnosis of mental illness, that I would have been forever skeptical of a neat biochemical marker. A chemical modification of DMPEA that has been explored in this question of pink spots, mental pathology, and diagnostic markers, is the corresponding acetamide. One of the metabolites of DMPEA was found to be the N-acetyl deriva-tive, N-acetyl-3,4- dimethoxyphenethylamine. It was found to be demethylated in man, and to have pharmacological activity in animals. Maybe this was the active compound that could be involved in the schizophrenic process. But human trials with it, as with the principal metabolite 3,4-dimethoxyphenylacetic acid, showed nothing at all in man. Another chemical modification is the beta-hydroxy analogue of DMPEA. It has been explored separately, and is the subject of its own recipe, in its own rights. See DME. Pink was not the only colorful spot associated with schizophrenia. Somewhere at about this same time, a research paper from Canada reported the observation of a mauve spot in the chromatographic analysis of urines of schizophrenic patients. This had nothing to do with DMPEA. I was working closely with a researcher at the psychiatric institute and we were fascinated by, again, a possible diagnostic marker. We assayed the urines of the next 10 patients being admitted as acute schizophrenics. No trace of mauve. We wrote to Canada, and verified the analytical procedure. We were told that the whatzis should have been added after, rather than before, the whosey, and that we should have heated for 30, not 10 minutes. Okay. We assayed the urines of the next 10 patients being admitted using these new directions. No trace of mauve. Another call to Canada, and we were informed that we still werenUt doing it right. They were consistently batting a 100% positive correlation between mauve spots and schizophrenics, and 0% with healthy controls. In fact, they actually gave this positive test the name of a disease, Malvaria. Then, that little burst of insight! Aha! What if, just what if, they had been seeing something given to their schizophrenics? Chlorpromazine was the popular treatment of the day. We took a whopping dose of chlorpromazine, and over the next couple of days did manage (barely) to collect our urine samples. Both of us were positive Malvarians! And three days later, we were again negative. We were most likely seeing a metabolite of chlorpromazine. One last call to Canada with the ultimate question Q had you given any medication to your schizophrenics before your urine analysis? Of course (came the answer) Q it would not be ethical to leave them untreated. Another color down the drain, and still no objective measure for mental illness. By the way, I cannot say I like the chlorpromazine trip. There is no real communication either with others or with yourself, with that stuff. You are a zombie, but if you are both schizophrenic and a zombie, you cannot possibly be troublesome for anybody in the emergency room. #61 DOAM; 2,5-DIMETHOXY-4-(n)-AMYLAMPHETAMINE SYNTHESIS: A solution of 110 g p-dimethoxybenzene and 102 g valeric acid in 168 g polyphosphoric acid was heated on the steam bath for 3 h, giving a deep red homogeneous solution. This was poured into 1 L H2O with good stirring. The strongly acidic, cloudy suspension was extracted with 3x200 mL CH2Cl2, the extracts pooled, washed with 4x150 mL 5% NaOH, and finally once with dilute HCl. The solvent was removed under vacuum, and the residual amber oil cooled overnight at 0 !C. Some 30 g of crystalline, unreacted dimethoxybenzene were removed by filtration, and the 85 g of residual oil distilled at the water pump. Another 15 g of di-methoxybenzene came over as an early cut, but the fraction boil-ing at 184-192 !C (mostly 188-192 !C) weighed 53.0 g and was reasonably pure 2,5-dimethoxyamylophenone. The reaction of the acid chloride of valeric acid with p-dimethoxybenzene and anhydrous AlCl3 in CH2Cl2 (parallel to the preparation of the butyrophenone analog, see DOBU) gave an inferior yield (23.2 g from 92 g dimethoxybenzene), but did provide a sizeable sample (12.2 g) of 2-hydroxy-5-methoxyamylophenone from the basic washes of the crude reaction mixture. This pale yellow solid, after recrystallization from MeOH, had a mp of 62-62.5 !C. Anal. (C12H16O3) C,H. To 360 g mossy zinc there was added a solution of 7.2 g mercuric chloride in 200 mL warm H2O, and this was swirled periodically for 2 h. The H2O was drained off, and the amalgamated zinc added to a 2 L three-neck round-bottomed flask, treated with 200 mL concentrated HCl, and heated with an electric mantle. A solution of 53.0 g of 2,5-dimethoxyamylophenone in 107 mL EtOH containing 30 mL concentrated HCl was added drop-wise over the course of 4 h accompanied by 330 mL of concentrated HCl added batchwise over this same period. The mixture was held at reflux overnight and, after cooling, diluted with sufficient H2O to allowed CH2Cl2 to be the lower phase. The phases were separated, and the aqueous phase was extracted with 2x200 mL additional CH2Cl2. These organic phases were combined, washed first with 5% NaOH and then with H2O, and the solvent removed under vacuum. Distillation at the water pump yielded two fractions. The first distilled from about 100-130 !C, weighed 8.8 g, had a faint smell of apples and fennel, and was free of a carbonyl group in the infra-red. It proved to be only 50% pure by GC, however, and was discarded. The major fraction was a pale amber oil distilling between 152-170 !C and was substantially free of smell. It weighed 18.9 g, and was (by GC) 90% pure 2,5-dimethoxy-(n)-amylbenzene. A mixture of 36.3 g POCl3 and 40.9 g N-methylformanilide was allowed to incubate for 0.5 h. To this there was then added 18.5 g of 2,5-dimethoxy-(n)-amylbenzene and the mixture heated on the steam bath for 2 h. This mixture was poured into a large quantity of H2O and stirred overnight. The black oily product was extracted with 3x100 mL CH2Cl2, and the extracts combined and stripped of solvent under vacuum. The black residue was distilled at 180-205 !C at 20 mm/Hg to give 12.5 g of a pale amber oil that slowly set up to a crystalline mass. An analytical sample was recrystallized from MeOH to provide 2,5-dimethoxy-4-(n)-amylbenzaldehyde with a mp of 25-26 !C. Anal. (C14H20O3) H; C: calcd, 71.16: found, 71.92, 71.74. A solution of 12.3 g 2,5-dimethoxy-4-(n)-amylbenzaldehyde in 50 mL acetic acid was treated with 4.0 g anhydrous ammonium acetate and 12 mL nitroethane. This mixture was heated on the steam bath for 4 h, then poured into a large quantity of H2O. This was extracted with 3x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed to give a deep red oil that, on standing in the refrigerator, slowly set to a crystalline mass weighing 13.5 g. An analytical sample was recrystallized from MeOH to provide 1-(2,5-dimethoxy-4-(n)-amylphenyl)-2-nitropropene as fine yellow microcrystals with a mp of 44 !C sharp. Anal. (C16H23NO4) C,H,N. To a gently refluxing suspension of 10 g LAH in 500 mL anhydrous Et2O under a He atmosphere, there was added by 13.2 g 1-(2,5-dimethoxy-4-(n)-butyl-phenyl)-2-nitropropene by allowing the condensing ether drip into a Soxhlet thimble containing the nitrostyrene which effectively added a warm saturated solution of it dropwise to the reaction mixture. Refluxing was maintained for 18 h, and the cooled reaction flask stirred for several additional days. The excess hydride was destroyed by the cautious addition of 1 L 8% H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and the aqueous layer was washed with an additional 2x100 mL Et2O. Removal of the solvent from the organic phase and washings provided 4.7 g of a thick red oil that was discarded. The aqueous phase was then extracted with 2x200 mL CH2Cl2 which actually removed the product as the sulfate salt. This organic phase was washed with 2x100 mL 5% K2CO3 (removing the H2SO4) and with the evaporation of the solvent there was obtained 6.2 g of an oily amber residue. This was dissolved in 200 mL Et2O and saturated with anhydrous HCl gas. Fine white crystals of 2,5-dimethoxy-4-(n)-amylamphetamine hydrochloride (DOAM) separated, were removed by filtration, Et2O-washed and air dried, and weighed 5.2 g. The mp of 136-139 !C was increased to 145-146 !C by recrystallization from CH3CN. Anal. (C16H28ClNO2) C,H,N. DOSAGE: greater than 10 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 10 mg) There was a clear threshold that in no way interfered with my day's activities. I was quite gay and voluble at lunch and bubbled on into the afternoon with puns and high spirits. There may have been a little motor incoordination as noted in handwriting, and there was a strange tenseness during driving. There were no sequelae, there was no trouble sleeping, and with this potency way down from the lower homologues, I have no pressing desire to take this compound to a higher dose. EXTENSIONS AND COMMENTARY: The actual procedure that was published for the isolation of this final amine was a different one, one that would certainly work, but which was based on the procedures tried and proven with the lower homologues. The process described above is just a bit bizarre (a sulfate salt extracting into methylene chloride) but it was the actual thing that was done. The work was started towards two additional compounds but these never got past the first Rketone and phenolS stage. p-Dimethoxybenzene was brought into reaction with n-caproic acid with polyphosphoric acid (aiming towards 2,5-dimethoxy-4-(n)-hexylamphetamine, DOHE) but this was dropped when DOAM proved to be down in potency. And the reaction between p-dimethoxybenzene and benzoyl chloride with anh. aluminum chloride went well (aiming towards 2,5-dimethoxy-4-benzylamphetamine, DOBZ). A goodly amount of the phenol (2-hydroxy-5-methoxybenzophenone) was obtained as fine yellow crystals, but this line of inquiry was also dropped. The preparation of DOAM was, as a matter of fact, the last of the homol-ogous series of compounds actually completed, which stemmed from the original discovery of DOM. The RTen Classic LadiesS concept was mentioned under ARIADNE, and the adding of a methyl group in the place of a hydrogen atom at the 4-position-methyl led to the synthesis of Ms. HECATE and gave rise to DOET. The whole series of methyl-ethyl-propyl-butyl-amyl compounds was appealing to me, in that the potency seemed to increase initially as the chain got longer, and then it abruptly dropped off. WouldnUt it be nice, I thought, if I could interest some pharmacologist in looking at this tight set of drugs with some animal model, to see if there is some neurotransmitter activity that would show a parallel action. I learned of a curious young researcher in Washington who had an elegant procedure for measuring serotonin agonist action using the (otherwise) discarded sheep umbilical artery strips. These become available each year at lambing time, do not cost the life of anything, and require very little compound. He assayed my compounds and, lo and behold, the serotonin activity also went through a maximum in the middle of this series. We published a short paper to this effect, which served as a excellent vehicle to get the cogent human data into the scientific literature. I have never understood the reasons that there might be connection between the twitching of a umbilical artery in a sheep and the appearance of an insight in the mind of man. And, I have never personally met this pharmacologist. Some day, I hope to do both. #62 DOB; 2,5-DIMETHOXY-4-BROMOAMPHETAMINE SYNTHESIS: To a well-stirred solution of 1.95 g of the free base of 2,5-dimethoxyamphetamine (2,5-DMA) in 12 mL glacial acetic acid, there was added 1.8 g elemental bromine dissolved in 4 mL acetic acid over the course of 5 min. The slightly exothermic reaction was allowed to stir for 3 h, and then added to about 200 mL H2O. The cloudy solution was washed with 2x100 Et2O, made basic with aqueous NaOH, and extracted with 3x100 mL CH2Cl2. Evaporation of the solvent from the pooled extracts gave about 3 mL of a pale amber oil which was dissolved in 250 mL anhydrous Et2O and saturated with anhydrous HCl gas. The fine white crystals of 2,5-dimethoxy-4-bromoamphetamine hydrochloride, DOB, were removed by filtration, Et2O washed, and air dried. These weighed 1.7 g and had a mp of 195-196 !C. Recrystallization from IPA brought this up to 207-208 !C. Proton NMR spectroscopy of the hydrochloride salt in D2O gave confidence that the bromine atom had uniquely entered the 4-position, in that there were only two unsplit aromatic hydrogen atoms present, at 6.97 and at 7.20 ppm downfield from external TMS. DOSAGE: 1.0 - 3.0 mg. DURATION: 18 - 30 h. QUALITATIVE COMMENTS: (with 0.4 mg) There was a distinct enhancement of visual perception, and some strengthening of colors. A clean, cold feeling of wind on the skin. I felt an enriched emotional affect, a comfortable and good feeling, and easy sleeping with colorful and important dreams. (with 2.0 mg) There was a continuous tremor at the physical level, and an incredible Moebius strip representation of reality at the intellectual level. I was able to enter into personal problems easily, and get out again when I chose to. During the next day, there were brief lapses of attention, or little fugue states, and it was not until the following evening that I was completely myself again. (with 2.8 mg) About three hours into this I had a severe cramp, and had a near fainting response to the pain, and yet there was no pain! I felt that I was very near a loss of consciousness, and this was most disturbing. There were flashes of depersonalization. I saw rings around the moon with prismatic colors, and there were long-lasting Rafter-imagesS following any viewings of points of light. I was still a good plus 1 at 14 hours, but did manage to sleep. It was the next day before I was again at baseline. (with 3.0 mg) This was a complex, but a very good day. It involved making a large pot of chicken-vegetable soup, and listening to H.L., my favorite Saturday morning fundamentalist Christian radio preacher, bless Tim. The Democrats are not exactly all anti-American dupes of Moscow (or the Devil), but to H.L., they are practically, almost, next-door to it. The Rapture is supposed to happen tomorrow according to a certain book, newly published (just in time, looks like) and he is busy softening the possible disappointment of those who may find themselves unchanged Monday morning. Wunnerful. It's been one heck of a good experiment, and I canUt understand why we waited nine years to try this gorgeous stuff. Without going into the cosmic and delicious details, let's just say itUs a great material and a good level. (with 0.5 mg of the RRS isomer) I am underway, and this is a smooth intoxication. I am completely functional, but still really a plus two. I would not choose to drive a car. Not very far. I felt a rather quick dropping to a plus-one at the fifth hour, but there is a residual stimulation still the following morning. (with 1.0 mg of the RRS isomer) By the fourth hour I am absolutely a +++ and am searching the kitchen for food. But what I eat is only so-so. There is not the introspection or intensity of 2.0 milligrams of the racemate material, but this is a rewarding place nonethless. At the 18th hour, there was some fitful sleep, with bizarre dreams. The next day I was still hungry for altered spaces, and successfully challenged the residual plus one with LSD and, as is usually the case, acid cut right through the detritus and allowed a direct shot up to a +++ again. (with 1.5 mg of the RRS isomer) This is a +++ but it is vaguely irrational. I feel a heavy body load, but then the temperature outside is over a hundred degrees and I may not be in the best of all physical environments. I would not wish any higher dosage. There were cat-naps at the twelth hour, but most symptoms were still there at the 18th hour. A good experience. It would be interesting to compare this, some day, with 3.0 milligrams of the racemate. (with 0.5 mg of the RSS isomer) There are no effects at all. (with 1.0 mg of the RSS isomer) There is something warm and nice at a couple of hours into this, but I am no more than threshold, and the effects are very slight. By the fifth hour there are no longer any effects. EXTENSIONS AND COMMENTARY: The stars had clearly lined up in favor of making DOB and exploring its biological activity. This preparation had been completed in 1967 and the report of this compound and its unprecedently high potency published in 1971. And very shortly, two additional papers appeared completely independently. One described DOB made via a different route, and describing high activity in rats. The other described DOB and a couple of closely related brominated amphetamines and their action in man. This is one of the last of the experimental compounds within the phenethylamine family on which any animal toxicity studies were performed by me prior to human studies. A mouse injected with 50 mg/Kg (ip) showed considerable twitching and was irritable. Another, at 100 mg/Kg (ip), had overt shaking at 20 minutes, which evolved into persistent hyperactivity that lasted several hours. Yet another, at 125 mg/Kg (ip), lost much of her righting reflex within 15 minutes, entered into convulsions at 50 minutes, and was dead a half hour later. A fourth mouse, at 150 mg/Kg (ip), entered into spontaneous convulsions within 10 minutes, and expired in what looked like an uncomfortable death at 22 minutes following injection. What was learned? That the LD/50 was somewhere between 100 and 125 mg/Kg for the mouse. And an effective dose in man of maybe 2 mg (for an 80 Kg man) is equivalent to 25 ug/Kg. Therefore the index of safety (the therapeutic index, the lethal dose divided by the effective dose) is well over a thousand. I feel that two mice were killed without anything of value having been received in return. Actually, it is very likely that the damaging, if not lethal, level of DOB in man is a lot lower than this ratio would imply. There was a report of a death of a young lady following the snorting of an amount of DOB so massive, there was the actual recovery of over nine milligrams of the drug from her body tissues in the post-mortem examination. It was said that she and her companion had thought that the drug they were using was MDA and, taking a dosage appropriate for this, effectively overdosed themselves. He survived, following convulsions and an extended period (several weeks) of being in a comatose state. Tragic examples have been reported that involve arterial vascular spasm. But in most overdose cases ascribed to DOB, the identity of the drug has remained unestablished. As with DOI, the presence of a heavy atom, the bromine atom, in DOB makes the radioactive isotope labelled material a powerful research tool. Studies with DOB labelled with either 82Br or 77Br have been used in human subjects to follow the distribution of the drug. The use of a whole body scanner permits the imaging of the intact body, with the travelings of the radioactivity easily followed from outside. A fascinating finding is that DOB goes first and foremost to the human lung where it accumulates for a couple of hours. It is only afterwards that the brain level builds up. There is a strong implication that some metabolic conversion occurs in the lung, and it is only after this that the truly active metabolite is available for central action. This is consistent with the relatively slow onset of effect, and the very long duration of action. As with all the other psychedelics which can and have been studied as their optical isomers, it is the RRS isomer of DOB that is the more active than the racemic mixture, and the RSS is certainly much less active, but it has never been run up to fully active levels. The alpha-ethyl homologue of DOB is mentioned under ARIADNE. The positionally rearranged isomers of DOB are discussed under META-DOB. #63 DOBU; 2,5-DIMETHOXY-4-(n)-BUTYLAMPHETAMINE SYNTHESIS: A well stirred suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was treated with 102 g butyryl chloride. This mixture was added in small portions, over the course of 20 min, to a well-stirred solution of 110.4 g p-dimethoxybenzene in 300 mL CH2Cl2. After an additional 1 h stirring, the mixture was poured into 1 L H2O, and the two phases separated. The aqueous phase was extracted with 2x100 mL CH2Cl2, and the organic fractions pooled. These were washed with 4x125 mL 5% NaOH which removed both unreacted butyric acid as well as a small amount of 2-hydroxy-4-methoxybutyrophenone. Removal of the CH2Cl2 under vacuum gave 156.7 g of a residue that was distilled at 170-178 !C at the water pump. The isolated 2,5-dimethoxybutyrophenone was a pale yellow oil that weighed 146 g and was about 85% pure by GC analysis. The principal impurity was unreacted dimethoxybenzene. The identical preparation with CS2 as a solvent, rather than CH2Cl2 gave a somewhat smaller yield of product. To 150 g mossy zinc there was added a solution of 3 g mercuric chloride in 60 mL H2O, and this was swirled periodically for 2 h. The H2O was drained off, and the amalgamated zinc added to a 1 L three-neck round-bottomed flask, treated with 80 mL concentrated HCl, and heated on the steam bath. A solution of 20.8 g of 2,5-dimethoxybutyrophenone in 45 mL EtOH containing 10 mL concentrated HCl was added in increments over a 4 h period. During this period an additional 140 mL of concentrated HCl was added periodically to the ketone solution. Heating was maintained for an additional 4 h. After cooling, the aqueous filtrate was extracted with 3x100 mL CH2Cl2 and these pooled extracts washed with 2x200 mL 5% NaOH to remove a small amount of phenolic impurity. After removal of the solvent under vacuum, the residual 16.1 g of clear oil was distilled over the 100-160 !C range (largely at 141-145 !C) at the water pump to give 10 g of 2,5-dimethoxy-(n)-butylbenzene as a white oil. This was about 90% pure by GC analysis, and was used without further purification in the next step. A mixture of 98 mL POCl3 and 108 mL N-methylformanilide was allowed to incubate for 0.5 h. To this there was then added 47.3 g of 2,5-dimethoxy-(n)-butylbenzene and the mixture heated on the steam bath for 1.5 h. This mixture was poured into 1 L H2O and stirred overnight. The H2O was drained from the extremely gooey black crystals that were formed, and extracted with 2x100 mL portions of hexane. The black residue was diluted with these extracts and, on slow evaporation there was deposited 26.4 g of oily amber crystals. Filtering these through a medium porous funnel and sucking the oily phase away from the solids yielded 14.8 g of yellow crystals that could be recrystallized from 50 mL MeOH to give, after filtration and air drying to constant weight, 6.4 g of 2,5-dimethoxy-4-(n)-butylbenzaldehyde as pale yellow crystals with a mp of 47-48 !C. The recovery of all organic soluble things from the above process gave, after removal of the extraction solvents and making boiling hexane extractions of the residues, a second crop of aldehyde of equal weight and of identical mp. An analytical sample, from hexane, had the same mp. Anal. (C13H18O3) C,H. A solution of 13.2 g 2,5-dimethoxy-4-(n)-butylbenzaldehyde in 50 mL acetic acid was treated with 4.0 g anhydrous ammonium acetate and 10 mL nitroethane. This mixture was heated on the steam bath for 4 h, then poured into a large quantity of H2O. This was extracted with 2x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed to give 19 g of a deep red oil. This was dissolved in 35 mL hot MeOH and slowly cooled, depositing yellow-orange crystals. These were removed by filtration, washed with cold MeOH, and air-dried to constant weight. Thus there was obtained 11.8 g of 1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene with a mp of 54-56 !C. Recrystallization of an analytical sample from MeOH tightened the mp to 55-56 !C. Anal. (C15H21NO4) C,H,N. To a gently refluxing suspension of 8.5 g LAH in 300 mL anhydrous Et2O under a He atmosphere, there was added 11.0 g 1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene by allowing the condensing ether to drip into a Soxhlet thimble containing the nitrostyrene, thus effectively adding a warm saturated solution of it dropwise. Refluxing was maintained overnight, and the cooled reaction flask stirred for several additional days. The excess hydride was destroyed by the cautious addition of 600 mL H2O containing 55 g H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 250 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was above 9, and this was then extracted with 3x200 mL CH2Cl2. Evaporation of the solvent produced 12 g of an amber oil that gelatinized to a waxy, amorphous mass. This was leached as thoroughly as possible with anhydrous Et2O which was clarified by filtration, then saturated with anhydrous HCl gas. After a few minutes delay, there commenced the separation of fine white crystals of 2,5-dimethoxy-4-(n)-butylamphetamine hydrochloride (DOBU). These weighed, after filtration, Et2O washing, and air drying to constant weight, 5.8 g. Recrystallization from boiling CH3CN (this is an unusually exothermic crystallization) yielded 5.4 g of a fluffy white product with mp 151-152 !C. Anal. (C15H26ClNO2) C,H,N. DOSAGE: uncertain. DURATION: very long. QUALITATIVE COMMENTS: (with 2.2 mg) It was almost the fourth hour before I noticed something. Then I felt an increasing manic intoxication, winding up tighter and tighter. Sleep was impossible until some 18 hours after the start of the trial. There was some paresthesia, but no mydriasis. This might be a stimulant, but it is not a psychedelic, at least at this level. Go up slowly. (with 2.8 mg) Nothing for over seven hours. Then there was what seemed to be an irritability and shortness of temper. Mentally I am completely clear, but no more alert than usual. There was no sleep that evening, and the next day there was a feeling of overall depression. Perhaps that was due to the lack of sleep, but there were no signs of residual sleepiness. EXTENSIONS AND COMMENTARY: It is not possible to give a dosage range for DOBU. There is no question but that whatever is occurring is slow of onset, and very long lived. In general, the effects resemble stimulation more that anything else. A butyl group has four carbons, and they can be interconnected in four ways (as long as you donUt connect them in rings). If all four of them are in a straight chain, you have the so-called normal butyl (or n-butyl) group, and this is the exact arrangement that is found in the DOBU. The atoms can be numbered #1 through #4, going outwards from the point of attachment. The chain can, however, be only three carbons long, and the fourth or extra carbon attached on the #2 carbon atom; this is called the iso-butyl (or i-butyl) group. Or the extra left-over carbon can be attached to the #1 carbon atom; this is called the secondary butyl (or sec-butyl or s-butyl) group. Or lastly, the atoms can be all scrunched up, with the chain only two carbons long, and the other two left-over methyl carbons attached to the #1 carbon atom. This isomer is called the tertiary butyl (or tert-butyl or t-butyl) group. In animal studies, and in preliminary human studies, the activity of these compounds drops as the butyl group gets more and more scrunched. The isomer with the iso-butyl group has been synthesized by the Friedel- Crafts reaction of isobutyryl chloride with p-dimethoxybenzene, followed by reduction of the ketone to an alcohol, dehydration to a dimethylstyrene, and final hydrogenation to a hydrocarbon. The formation of the benzaldehyde, reaction with nitroethane, and final lithium aluminum hydride reduction to 2,5-dimethoxy-4-(2-methylpropyl)-amphetamine hydrochloride (DOIB, mp 164-166 !C) were completely conventional. In drug discrimination studies in rats, DOIB was only a third as active as DOM, and in humans the activity falls in the 10 to 15 milligram area. The isomer with the sec-butyl group was made in a somewhat similar manner, from 2,5-dimeth-oxyacetophenone. The addition of ethyl magnesium bromide gave an alcohol which with dehydration yielded a pair of dimethylstyrenes isomeric to the compound mentioned above. From there an identical sequence of steps (hydrogenation, benzaldehyde synthesis, nitrostyrene, and lithium aluminum hydride reduction) produced 2,5-dimethoxy-4-(1-methylpropyl)amphetamine hydrochloride (DOSB, mp 168-170 !C.). In the rat studies it was only a twelfth the potency of DOM, and in man the active dose is in the 25 to 30 milligram area. As with the normal butyl compound, there is a strong stimulation factor, with real and long-lasting sleep disturbance. The last of the butyl isomers, the tert-butyl compound, was made from a much more obvious starting material. This is the commercially available tert-butyl hydroquinone. It was methylated in sodium hydroxide with methyl iodide, and then carried through the above sequence (benzaldehyde. mp 124 !C from cyclohexane, nitrostyrene, yellow crystals from methanol, mp 95-96.5 !C, and lithium aluminum hydride reduction) to give 2,5-dimethoxy-4-(1,1-dimethylethyl)amphetamine hydrochloride (DOTB, mp 168 !C). Rats trained in a process called the Sidman Avoidance Schedule gave behavior that suggested that DOTB had no activity at all, and in human trials, doses of up to 25 milligrams were totally without effect. An effort was made to prepare a butyl analogue containing a ring, but it was never completed. This was the cyclopropylmethyl isomer, 2,5-dimethoxy-4-cyclo-propylmethylamphetamine hydrochloride, DOCPM. Only the first step of its synthesis was complete (the reaction of cyclopropylcarboxylic acid chloride with p-dimethoxybenzene) and even it went badly. The desired ketone (2,5-dimethoxyphenyl cyclopropyl ketone) was most difficult to separate from the recovered starting ether. A promising approach would be the isolation of the phenol (2-hydroxy-5-methoxyphenyl cyclopropyl ketone) which is a beautiful yellow solid with a melting point of 99-100 !C from methanol. Anal. (C11H12O3) C,H. It then could be methylated to the wanted intermediate. It is the major product when the reaction is conducted with anhydrous aluminum chloride in methylene chloride. The 2-carbon phenethylamine homologues of these compounds could all, in principle be easily made by using nitromethane instead of nitroethane with the intermediary benzaldehydes. But, as of the present time, none of them have been made, so their pharmacology remains completely unknown. #64 DOC; 2,5-DIMETHOXY-4-CHLOROAMPHETAMINE SYNTHESIS: A solution of 6.96 g 2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) in 250 mL H2O was made basic with aqueous NaOH and extracted with 3x75 mL CH2Cl2. After removal of the solvent from the pooled extracts under vacuum, the residual free base was dissolved in 36 g glacial acetic acid and, with good stirring, cooled to 0 !C with an external ice bath. There was then added, with a Pasteur pipette, 3 mL of liquid chlorine. The generation of HCl was evident, and the reaction was allowed to stir for an additional 3 h. The mixture was then poured into 300 mL H2O and washed with 3x100 mL Et2O. The aqueous phase was made basic with NaOH and extracted with 3x150 mL CH2Cl2. After removal of the solvent from the pooled extracts, the residue was dissolved in Et2O and saturated with anhydrous HCl gas. There was the formation of a heavy oily precipitate. The ether supernatent was decanted, and the residue was intimately mixed with 200 mL of fresh anhydrous Et2O. Everything set up as an off-white crystalline mass weighing 2.3 g. This was dissolved in 12 mL of boiling MeOH and diluted with 230 mL boiling Et2O. The clear solution was quickly filtered to give a clear, pale amber mother liquor, which soon started depositing lustrous white crystals. After filtering, Et2O washing, and air drying to constant weight, there was obtained 1.4 g of 2,5-dimethoxy-4-chloroamphetamine hydrochloride (DOC) From the mother liquors (from the original HCl saturation) an equal amount of product could be obtained by exploiting the acetone insolubility of the hydrochloride salt of the product. The published mp of this salt, from acetone/EtOH, is 187-188 !C. A sample of this hydrochloride salt, prepared from the amino analogue via diazotization and eventual hydrolysis of an acetylated precursor, was recrystallized from EtOH/ether and had a mp of 193-194.5 !C. DOSAGE: 1.5 - 3.0 mg. DURATION: 12 - 24 h. QUALITATIVE COMMENTS: (with 1.6 mg) I was hit with a slightly light head; the effects were quite real. I was disconnected, and somehow spacey, but this was a favorable spacey which was kind of fun. Somewhere at about the sixth hour I realized that I was beginning to drop off a bit, but six hours later yet, there was still a lot of memory. This is a long thing. (with 2.4 mg) This is what I might call an archetypical psychedelic. Everything is there in spades, with few if any of the subtle graces, the Tgentle imagesU and Tgentle fantasiesU of the 2-carbon phenethylamines. This is the works. There are visuals, and there are interpretive problems with knowing just where you really are. The place where nothing makes sense, and yet everything makes sense. I have just slept for a few hours, and now I am awake and it has been eighteen hours, and there is a lot still going on, although I have a relaxed, good feeling. Anyone who uses this had better have 24 hours at their disposal. (with 2.4 mg) Here I am at the sixth hour, and I am still roaring along at a full plus three. I have established that this material is neither anti-erotic nor anorexic. The body is very comfortable, and so is the mind. There is an interesting aspect, perhaps peculiar only to this experiment and under these conditions. With my eyes closed the fantasy is a completely dark screen, lovely and seductive, subtle, and yet light must be deliberately brought in. This is not in any way negative for being in the dark, but is just unusual. I will have to try this in the daylight next time, to see what the eyes-closed brings to the mind-screen. At 24 hours, I have found that my sleep was not too great. My dreams were tight, and I kept defending against trouble; the nervous system was too alert. I was in a good humor, though, and I still am. This is excellent stuff, but start early in the day. EXTENSIONS AND COMMENTARY: It is clear that the three halo-amphetamine derivatives, DOI, DOB and DOC, are all pretty much of the same potency. And all of them very long lived. The difference between the various halogen atoms was brought up under the 2C-C discussion. DOC is clearly a long-lasting, dyed-in-the-wool psychedelic. In the making of this, by the procedures that have been followed in Canada, there are two chemical intermediates which might, some day, be looked at as potential psychedelics under their own colors. Reduction of the compound that is called DON in this Book II (2,5-dimethoxy-4-nitroamphetamine hydrochloride) with Pd/charcoal and hydrogen, gives the 4-amino derivative. This is 2,5-dimethoxy-4-aminoamphetamine dihydrochloride, DOA, which melts at 248-250 !C. And the reduction of an oxime intermediate gives rise to the acetamido analogue, 2,5-dimethoxy-4-acetamidoamphetamine hydrochloride, DOAA, with a mp of 249-250 !C. Neither compound has been tasted, but someday this omission will be corrected. DOA and DOAA have a sinister ring to them, however, and some changes of terminology might be needed. DOA, in the coroner's vocabulary, means Dead-On-Arrival. But then, AMA (the American Medical Association) just happens to also mean (in the jargon of emergency medicine) Against-Medical-Advice. Everything averages out, somehow. Remember that the amyl homolog (amyl at the 4-position) follows the 4-letter convention of all of the DOM homo-logues, and has the code name of DOAM. Thus, DOA, amino; DOAA, acetamido, and DOAM, amyl. One must learn to keep one's sense of humor. The immortal humorist Wavy Gravy once said, RIf you canUt laugh at life, it just isnUt funny anymore.S The code name of this compound, 2,5-dimethoxy-4-chloroamphetamine is, after, all, DOC. This should certainly appeal to some physicians. #65 DOEF; 2,5-DIMETHOXY-4-(2-FLUOROETHYL)- AMPHETAMINE SYNTHESIS: A well-stirred solution of 0.45 g free base DOB in 2 mL CH2Cl2 was treated with 0.37 g triethylamine, cooled to 0 !C, and there was then added a solution of 0.39 g 1,1,4,4-tetramethyl-1,4-dichlorodisilylethylene in 2 mL CH2Cl2. The reaction mixture was allowed to return to room temperature, with stirring continued for 2 h. The solvent was removed under vacuum, the residue suspended in hexane, and the insoluble by-products removed by filtration through celite. Removal of the solvent under vacuum gave 0.60 g 1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane as a gold-colored impure semi-solid mass which was used without further purification. To a solution of 0.60 g 1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane in 10 mL anhydrous Et2O under an inert atmosphere and cooled to -78 !C there was added 1.8 mL of a 1.7 M solution of t-butyl lithium in hexane. The resulting yellow solution was stirred for 20 min, and then treated with 1.65 mL of a 1.4 M solution of ethylene oxide in Et2O, the stirring was continued for 40 min, then the reaction mixture allowed to come to room temperature over an additional 40 min. There was added 20 mL hexane, and the temperature increased to 50 !C for an additional 2 h. The reaction mixture was treated with 3 mL H2O and diluted with 60 mL Et2O. The organic phase was washed with saturated NH4Cl, dried over anhydrous MgSO4, and after filtering off the inorganic drying agent, the organic solvents were removed under vacuum. The gold-colored residual oil was dissolved in 10 mL MeOH and treated with a 10% KOH. This mixture was heated for 30 min on the steam bath, returned to room temperature, and the volatiles removed under vacuum. The residue was dissolved in 3% H2SO4, washed twice with CH2Cl2, brought to pH 12 with 25% NaOH, and extracted with 3x50 mL CH2Cl2. The pooled extracts were combined, dried with anhydrous Na2SO4, and the solvent removed under vacuum to give 0.24 g of 2,5-dimethoxy-4-(2-hydroxyethyl)amphetamine (DOEH) as a white solid with a mp of 102-104 !C. To a suspension of 0.94 g DOEH in ice-cold anhydrous Et2O containing 1.4 g triethylamine, there was added 2.4 g trifluoroacetic anhydride dropwise over the course of 10 min. The reaction mixture was brought to reflux temperature, and held there with stirring for 1 h. After cooling, 60 mL of CH2Cl2 was added, and the organic phase washed with saturated NaHCO3. The solvent was removed under vacuum, providing a gold-colored solid as a residue. This was dissolved in 50 mL MeOH, diluted with 30 mL H2O and, following the addition of 0.76 g solid NaHCO3 the reaction mixture was stirred at room temperature for 3 h. The excess MeOH was removed under vacuum, and the remaining solids were suspended in CH2Cl2 and washed with H2O. After drying the organic phase with anhydrous Na2SO4 and removal of the solvent under vacuum, there was obtained 1.34 g 1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane as white solid with a mp of 129-131 !C. Anal. (C15H20F3NO4) C,H. A well-stirred solution of 0.09 g 1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane in 15 mL CH2Cl2 was cooled to -78 !C and treated with 0.05 g diethylaminosulfur trifluoride (DAST) added dropwise. The pale yellow reaction solution was stirred an additional 5 min and then brought up to room temperature and stirred for 1 h. There was then added (cautiously) 3 mL H2O followed by additional CH2Cl2. The phases were separated, the organic phase washed with H2O, dried with anhydrous Na2SO4 and, after filtering off the drying agent, stripped of solvent under vacuum. There was thus obtained 0.088 g of 1-[2,5-dimethoxy-4-(2-fluoroethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane as a white solid with a mp of 102-104 !C. A solution of 0.12 g 1-[2,5-dimethoxy-4-(2-hydroxyethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane in a mixture of 5 mL CH2Cl2 and 5 mL IPA was treated with 0.2 mL 2 N KOH, heated on the steam bath for 30 min, and then stripped of solvents under vacuum. The residue was suspended in CH2Cl2 and washed with 20% NaOH. The organic phase was dried with anhydrous Na2SO4 which was removed by filtration, and the combined filtrate and washings stripped of solvent under vacuum. The residual glass (0.08 g) was dissolved in IPA, neutralized with concentrated HCl and diluted with anhydrous Et2O to provide 2,5-dimethoxy-4-(2-fluoroethyl)amphetamine hydrochloride (DOEF) as a white crystalline solid with a mp of 205-208 !C. Anal. (C13H21ClFNO2) C,H. DOSAGE: 2 - 3.5 mg. DURATION: 12 - 16 h. QUALITATIVE COMMENTS: (with 2.2 mg) Somewhere between the first and second hour, I grew into a world that was slightly unworldly. Why? That is hard to say, as there was no appreciable visual component. I just knew that the place I was in was not completely familiar, and it was not necessarily friendly. But it was fascinating, and the music around me was magical. Time was moving slowly. I had to drive across the bay at about ten hours into this, and I was comfortable. That evening I slept well, but my dreams were pointless. (with 3.0 mg) It took almost three hours to full activity. The first signs of effects were felt within a half hour, but from then on the progress was slow and easy, without any discernible jumps. There was absolutely no body discomfort at all. Completely comfortable. There was a general humorousness about my state of mind which is always a good sign. We went to the bedroom at the two and a half hour point, and proceeded to establish that the material is far from anti-erotic. Beautiful response, without a mention of any feeling of risk at orgasm. I myself was not able to reach orgasm until about 5th to 6th hour, and then it was full and exceptionally delicious. So was the second one, a couple of hours later, if I remember correctly. All systems intact, body, mind and emotion. Gentle. Good for writing. No dark corners apparent at all. For me, not highly visual. Would take again, higher. (with 3.0 mg) There was no body threat at any time Q very comfortable. Good eyes closed, with complex imagery to music, but not too much with eyes-open. My attention span is relatively short, and easily diverted into new directions Q all quite reminiscent of DOI both as to dosage and effect. At 13 hours, I am still too alert to sleep, but a couple of hours later, OK. In the morning there is still a trace of something going on. This was a valid +++. EXTENSIONS AND COMMENTARY: I was asked by a student of mine a while ago, when I told him of this material, just why would anyone just happen to place a fluorine atom at the end of the 4-ethyl group of DOET? It wasnUt the sort of thing that someone would just happen to do. If there were a rationale, then that's fine. But by capricious impulse, no. But there is a rationale of sorts, which I just hinted at in the discussion under 2C-T-21. This argument of reason goes as follows. Assume that I would like to put a fluorine atom into a drug that does not normally have one. Why would I want to? Because I want to have the molecule carry a radioactive fluorine atom into some inner recess of the brain. Why? Because by using a positron-emitting fluorine I could possibly visualize the area of the brain that the drug went to. And if it went there in some abnormal way, the exact measure of that abnormality might give some clue as to potential brain misfunctioning. But, if you put a fluorine atom on a drug, it becomes a totally new drug and, quite reasonably, a pharmacologically different drug. However, a body of evidence is being accumulated that if a halogen, such as a bromine or an iodine atom, is replaced by a beta-fluoroethyl group, the electronic and polar properties of the drug can be pretty much the same. So, what psychedelics have a bromo or an iodo group? Obviously, DOB and DOI. Thus, DOEF is a natural candidate for fluorine-18 positron emission tomography, and also a natural candidate for clinical trials. And, voila, it is an active material. And IUll bet you dollars to doughnuts, that if one were to make the two-carbon analog 2,5-dimethoxy-4-(2-fluoroethyl)-phenethylamine, it would be every bit as much a treasure and ally as is 2C-B or 2C-I. In fact, I am sure enough about this prediction that I am willing to name the stuff 2C-EF. It will be easily made from 2C-B by the same reaction scheme that was used above for DOEF. And I will even guess that its activity level will be in the 20-30 milligram area. #66 DOET; HECATE; 2,5-DIMETHOXY-4-ETHYLAMPHETAMINE SYNTHESIS: To a solution of 19.7 g 2,5-dimethoxy-4-ethylbenzaldehyde (see the recipe for 2C-E for its preparation) in 72 g glacial acetic acid there was added 6.5 g anhydrous ammonium acetate and 10.2 g nitroethane. After heating for 1.75 h on the steam bath, the reaction mixture was cooled in a wet ice bath, diluted with 10 mL H2O, and seeded with a small crystal of product. The yellow crystals were removed by filtration (7.6 g wet with acetic acid) and another 2.25 g was obtained from the mother liquors with additional H2O. The combined fractions were recrystallized from 25 mL boiling MeOH, to give 6.5 g fine yellow crystals of 1-(2,5-dimethoxy-4-ethyl)-2-nitropropene, with a mp of 67.5-68.5 !C. Anal. (C13H17NO4) C,H,N. A suspension of 6.5 g LAH in 500 mL well stirred anhydrous Et2O was held at reflux under an inert atmosphere, with the return of the condensed solvent passing through a Soxhlet thimble containing 6.5 g 1-(2,5-dimethoxy-4-ethylphenyl)-2-nitropropene. After the addition of the nitrostyrene was complete, the stirred suspension was maintained at reflux for an additional 18 h, then cooled to room temperature. The excess hydride was destroyed with 500 mL 8% H2SO4, added cautiously until the hydrogen evolution ceased, then at a speed that allowed the formed solids to disperse. The phases were separated, the aqueous phase washed once with Et2O, treated with 150 g potassium sodium tartrate, and finally made basic (pH >9) with 5% NaOH. This was extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue, 7.9 g of a clear oil, was dissolved in 100 mL anhydrous Et2O and saturated with anhydrous HCl gas. After standing at room temperature for 2 h, the crystalline 2,5-dimethoxy-4-ethylamphetamine hydrochloride (DOET) was removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 5.9 g of lustrous white crystal with a mp of 190-191 !C. Recrystallization from CH3CN or EtOAc increased the mp to 194-195 !C. Anal. (C13H22ClNO2) C,H,N. DOSAGE: 2 - 6 mg. DURATION: 14 - 20 h. QUALITATIVE COMMENTS: (with 1.0 mg) This was a very gentle, relaxing level, but there were no psychedelic effects that were apparent. Easy, and relaxed, and I am in no way intoxicated or turned on. But I was in the throes of my menstrual period, and the cramps (and the accompanying irritability) were completely knocked out. Perhaps this is why I felt so relaxed and at peace. (with 2.5 mg) There is much, too much, movement with my eyes closed. And an awful lot there with my eyes open. The movement on the concrete floor in the basement when I went downstairs for wood for the fireplace, was too much. I felt almost sea-sick. And I am having reality problems Q I cannot seem to find my centering point of reference. There has to be a place to pin myself down to, and it is not findable anywhere I look. And my legs are twitching, and feeling as if they are falling asleep, and I had a crawling sensation on my body, so the body is not at peace either. In the morning I was still ++, but there is a clear indication that I am repairing. Anyway, I survived the experience. This is definitely not my thing. (with 4 mg) Just after an hour into the experiment, I was surprised by the awareness of some effects Q I had forgotten that I had taken something. At the second hour, it was real, but subtle. As a psychotomimetic or STP-like thing, there is very little there. But as a mood energizer, it is really a ++ or more. The clinical literature is right Q none of the hallucinogenic effects, but one brings into play whatever one wants to. Worked at cleaning up the office until 11 PM. I slept well. This has none of the LSD or STP seriousness. (with 6 mg) The onset was slow, and subtle. But the effects are fully there in about three or so hours. Everything I smelled was vivid, as are all the colors and shapes; they are clean, beautiful, serenely self-contained. No visual movement. The eyes-closed fantasy images tend to take off on their own, however, and they are extremely rich. I donUt see any dark corners. I believe it might well be possible to be creative with this, and there is no suggestion of body depletion, of body load. (with 7 mg) A hot day. Unbelievably lovely erotic-to-divine, deep loving, open, not much visual, eyes-closed form-image-symbol. Sleep attempts very shallow, slight TthinnessU, with an anticipation of darts. Intellect and feeling-emotion area intact and functioning at all times. Next morning still at a plus one. Incredible material. Perhaps best at 6 to 7 milligrams, no higher due to body load. EXTENSIONS AND COMMENTARY: The original code for this compound was DOE, which was completely logical based on DOM being the methyl member of this series (DO for the removal of the oxygen, desoxy, and M for putting a methyl in its place). And the putting of the ethyl thence should be DOE. This was fine until it was pointed out to me by a close colleague that DOE was a classic abbreviation for desoxyephedrine, a synonym for methamphetamine. The pressure to add the RTS of the RETS of the ethyl was heightened by looking ahead to other members of the series. DOA became DOAM, DOE became DOET, but DOM was already too firmly set in popular usage. And, anyway, DOME really looked strange. The original publications of the action of DOM clearly documented the compound as being a psychedelic and one with a sizeable measure of potential abuse. And, it is not a surprise that it was quickly shuffled into a legal classification that effectively precluded any further study of it. So, when this immediate homologue of DOM was studied and discussed in the literature, all reported dosages were those that were at the lowest levels, and no disturbing hints of abusability were mentioned. And this particular homologue has so far escaped the attention and restrictive action of the drug enforcement agencies, although the specific wording of the Controlled Substance Analogue Enforcement Act of 1986 might make this point moot, at least as far as human trials are concerned. At modest levels, DOET has the reputation of being a cognitive enhancer and is largely free of those sensory distortions that would catch the attention of the authorities who cannot tolerate drugs that distort the senses. The higher levels mentioned here have never been put into the published literature. It must be noted that there is a considerable variation of individual responses to this material. The effective dose range stated is quite broad. Some people are quite sensitive. This is, after all, one of the Classic Ladies, namely HECATE. The young experimental subject who had the dramatic relief from menstrual cramps at the one milligram dose tried the compound again the following month, and again had complete relief. But another volunteer, also plagued with severe cramping at that particular time of month, found no relief at all. A 50% success rate. No one else has, to my knowledge, explored this particular property. #67 DOI; 2,5-DIMETHOXY-4-IODOAMPHETAMINE SYNTHESIS: A mixture of 14.8 g phthalic anhydride and 19.5 g of 2,5-dimethoxyamphetamine (2,5-DMA) as the free base was heated gradually to about 150 !C with an open flame. A single clear phase was formed with the loss of H2O. After the hot melt remained quiet for a few moments, it was allowed to cool to about 50 !C and then diluted with 100 mL of hot MeOH. The solution was stirred until homogenous, seeded with product, and then cooled in an ice bath to complete the crystallization. After removal of the product by filtration, washing sparingly with MeOH, and air drying, there was obtained 24.6 g of N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide as off-white crystals, with a mp of 105-106 !C. Anal. (C19H19NO4) C,H,N. To a solution of 2.0 g N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide in 15 mL warm acetic acid which was being vigorously stirred, there was added a solution of 1.2 g iodine monochloride in 3 mL acetic acid. This was stirred for 2 h at about 40 !C during which time there was a definite lightening of color, but no solids formed. The reaction mixture was poured into 600 mL H2O which produced a reddish glob floating in a yellow-orange opaque aqueous phase. The glob was physically removed, dissolved in 30 mL boiling MeOH which, on cooling in an ice bath, deposited off-white crystals. These were removed by filtration, washed with MeOH, and air dried to give 1.5 g of N-[1-(2,5-dimethoxy-4-iodophenyl)-2-propyl]phthalimide as fine white crystals with a slight purple cast. The mp was 103-105.5 !C and the mixed mp with the starting non-iodinated phthalimide (mp 105-106 !C) was depressed (85-98 !C). Extraction of the aqueous phase, after alkalinification, provided an additional 0.15 g product. Anal. (C19H18NO4) C,H,N. A solution of 0.75 g N-(1-(2,5-dimethoxy-4-iodophenyl)-2-propyl)phthalimide in 10 mL EtOH was treated with 0.3 mL of hydrazine hydrate, and the clear solution was held at reflux on the steam bath overnight. After cooling, there was a crystallization of 1,4-dihydroxyphthalizine that started as small beads but finally became extensive and quite curdy. These solids were removed by filtration and had a mp of about 340 !C (reference samples melted over a five to ten degree range in the area of 335-350 !C). The filtrate was dissolved in 100 mL CH2Cl2 and extracted with 2x150 mL 0.1 N HCl. The aqueous extracts were washed once with CH2Cl2, made basic with 5% NaOH, and extracted with 3x100 mL CH2Cl2. Removal of the solvent under vacuum gave 0.5 g of a colorless oil which was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was obtained, after filtration, and air drying, 0.35 g of 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) as white crystals that melted at 200.5-201.5 !C. This value did not improved with recrystallization. Anal. (C11H17ClINO2) C,H,N. DOSAGE: 1.5 - 3.0 mg. DURATION: 16 - 30 h. QUALITATIVE COMMENTS: (with 0.6 mg) There was a nice spacey light-headedness for a few hours, and time seemed to move quite slowly. Then a generic sadness came over me, as I reminisced about earlier days (recalling pleasures now gone) and wondered if I would be allowed to be here on the Farm when I am old and not important. There is so much to be done, and I cannot do it all, and no one else cares. My mood became present-day and healthy by about the seventh hour. (with 1.6 mg) The general nature of the experience was depressing, with a sad view of life. There was no way I could connect with my emotions. Even my sadness was vague. At about the ninth hour I decided that enough was enough, and this strangely disappointing about-plus-two was aborted with 125 micrograms of LSD. The emotions became present and living within a half hour. I was greatly relieved. The erotic was not a mechanical attempt but a deeply involved feeling with an archetype of orgasm easily available. It was shaped like a flower, richly colored, with an unusual RSS shape to it. This was a lovely end to a difficult day. (with 3.0 mg) This is a clear, clean psychedelic. The eyes-closed imagery is excellent, with clearly delineated patterns, pictures, and colors. Perfect for an artist, and next time IUll devote some time to painting. Total ease for the body, but no help for my smoking problem. I still want to smoke. And at sixteen hours into this I am still at 1.5+ but IUll try to go to bed anyway, and sleep. (with 3.5 mg) I was at a full crashing +++ for about three or four hours. There was none of the LSD sparkle, but there were moments of Tlight-headednessU where one could move sideways with reality. I could leave where I was right over there, and come over here and get a strange but authentic view of where the TthereU was that I had left. It would be out-of-body, except that the body came over here with me rather than staying there. This doesnUt make sense now, but it sure did then. There was no trace of body impact, and I slept late that evening, but with some guardedness due to the intense imagery. This was no more intense than with 3.0 milligrams, but it was a little bit more to the unreal side. (with 1.0 mg of the RRS isomer) There was a clear ++ from the second to the eighth hour, but somehow there was not quite the elegance or the push of the racemate. I was sensible, and managed to do several technical chores in a reasonable way. Easy sleep at 15 hours into it. (with 2.3 mg of the RRS isomer) The water solution of the hydrochloride salt has a slightly sweetish taste! I was at a +++ without question, but there was a slight down mood towards the end. And it lasted a really long time; I was distinctly aware of residual stuff going on, well into the next day. (with 6.3 mg of the RSS isomer) I was at a benign one-and-a-half plus at about two hours, and finally flattened out at a ++. Would I double this dose? Probably not, but half again (to 9 or 10 milligrams) would feel safe for a plus 3. By evening I was near enough baseline to drive into town for a social obligation, but even when trying to sleep later that night there was some residue of imagery; remarkably, it was all in slow motion. The fantasies were slow-paced and sluggish. It would have been interesting to have explored eyes-closed during the day. EXTENSIONS AND COMMENTARY: Again, as with every other psychedelic amphetamine analogue which has a chiral center and has been explored as the individual optical isomers, it is the RRS isomer that is the more potent. And again, the other isomer, the RSS isomer, still shows some activity. The same was true with DOB, and DOM, and MDA. The only exception was MDMA, but then that is more of a stimulant, and there is virtually no psychedelic component to its action. Rat studies, where there is a measure of the discrimination of a test compound from saline, have shown the RRS isomer to have about twice the potency of the RSS isomer. That the RRS is more potent is certain, but the above reports would suggest that the factor would be closer to times-four rather than times-two. A number of studies with DOI in animal models have shown it to have an extremely high binding capacity to what are called the 5-HT2 receptors. Serotonin is a vital neurotransmitter in the brain, and is strongly implicated in the action of all of the phenethylamine psychedelics. The place where it acts, at the molecular level, is called its receptor site. As an outgrowth of the cooperative studies of the medicinal chemists working closely with the neuropharmacologists, a number of compounds have emerged that interact with these sites. But this one interacts with these sites and not those, and that one interacts with those sites and not these. So, there has developed a collection of sub-divisions and sub-subdivisions of receptor sites, all related to serotonin, but each defined by the particular compound that interacts most tightly with it. Thus, there were serotonin R1S receptors, and then there were R1S and R2S receptors, and then R1a and R1bS and R2aS and R2bS receptors, and on and on. These are called 5-HT receptors, since the chemical name for serotonin is 5-hydroxytryptamine, and the scientist would never want to let the layman know just what he is talking about. DOI has been synthesized with a variety of radioactive iodine isotopes in it, and these tools have been of considerable value in mapping out its brain distribution. And by extrapolation, the possible localization of other psychedelic compounds that cannot be so easily labelled. A small neurochemical research company on the East Coast picked up on these properties of DOI, and offered it as a commercial item for research experiments. But I doubt that they are completely innocent of the fact that DOI is an extremely potent psychedelic and that it is still unrecognized by the Federal drug laws since, in their most recent catalog, the price had almost doubled and a note had been added to the effect that telephone orders cannot be accepted for this compound. The four-carbon butylamine homologue (the ARIADNE analogue) of DOI has been synthesized. A mixture of the free base of 1-(2,5-dimethoxyphenyl)-2-aminobutane (see preparation under DOB) and phthalic anhydride was fused, cooled, and recrystallized from either methanol or cyclohexane to give crystals of N-[1-(2,5-dimethoxyphenyl)-2-butyl]phthalimide with a melting point of 76-77 !C and an analysis (C20H21NO4) C,H,N. This was iodinated with iodine monochloride in acetic acid to give N-[1-(2,5-dimethoxy-4-iodophenyl)-2-butyl]phthalimide which was chromatographically distinct from the uniodinated starting material (silica gel, CH2Cl2 ), but which did not crystallize. This was treated with hydrazine hydrate in ethanol to provide 1-(2,5-dimethoxy-4-iodophenyl)-2-aminobutane hydrochloride which was crystallized from CH3CN/EtOH to give white crystals with a mp of 217-218.5 !C and an analysis (C12H19CINO2) C,H,N. This butyl homolog of DOI has been assayed at up to four milligrams, and is without any central effects whatsoever. An experiment with 12.4 microcuries of 131I labelled material with the whole body scanner showed most of it accumulating in the gut and liver, with almost none to the brain. For those who find such statistics interesting, the parent compound DOI vies with DOB as probably the most potent of the phenethylamine psychedelics as of the moment, and certainly one of the most long lived. A very important, centrally pivotal, and completely paradoxical compound in this area, is the N,N-dimethyl homologue of DOI, or 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA). This compound was the starting point of the study of a large number of homologues and it deserves, and has received, a separate recipe. #68 DOM; STP; 2,5-DIMETHOXY-4-METHYLAMPHETAMINE SYNTHESIS: To a solution of 54.9 g 2,5-dimethoxy-4-methylbenzaldehyde (see the recipe for 2C-D for its preparation) in 215 g glacial acetic acid there was added 19.5 g anhydrous ammonium acetate and 30.6 g nitroethane. This mixture was heated for 3 h on the steam bath, the reaction mixture was cooled in a wet ice bath, allowing the spontaneous formation of yellow crystals. As much H2O as possible was added (just short of a persistant cloudy oily character) and after a few additional h standing, the crystalline 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene was removed by filtration and recrystallized from boiling acetic acid. The yield, after drying to constant weight, was 28.3 g and the mp was 87-88 !C. Anal. (C12H15NO4) C,H,N. A suspension of 9.5 g LAH in 750 mL well stirred anhydrous Et2O was held at reflux under an inert atmosphere, with the return of the condensed solvent passing through a Soxhlet thimble containing 9.5 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene. After the addition of the nitrostyrene was complete, the stirred suspension was maintained at reflux for an additional 4 h, then cooled to room temperature and allowed to continue stirring overnight. The excess hydride was destroyed by the addition of 750 mL 8% H2SO4, cautiously, until the hydrogen evolution ceased, then at a speed that allowed the formed solids to disperse. The phases were separated, the aqueous phase washed once with Et2O, treated with 225 g potassium sodium tartrate, and finally made basic (pH >9) with 5% NaOH. This was extracted with 3x150 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was 9.6 g of a clear oil which spontaneously formed crystals with a mp of 60.5-61 !C from hexane. These solids were dissolved in 150 mL anhydrous Et2O, and saturated with anhydrous HCl gas. After standing at room temperature for 2 h, the crystalline 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) was removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 8.25 g of glistening white crystals that had a mp of 190.5-191.5 !C. The sulfate had a mp of 131 !C. Anal. (C12H20ClNO2) C,H,N. The above nitrostyrene may also be converted to the final amine product through the intermediary of the corresponding phenylacetone. To a well stirred suspension of 10.4 g powdered iron in 20 mL glacial acetic acid held at reflux temperature, there was added 4.9 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene as a solid. Refluxing was continued for 2 h and then all was filtered through wet Celite. After washing with 300 mL H2O followed by 300 mL Et2O, the combined filtrate and washes were separated, and the aqueous phase extracted with 2x100 mL Et2O. The organic phase and extracts were combined and washed with 2x100 mL saturated K2CO3 and the solvent was removed under vacuum yielding a reddish oil weighing 3.3 g. This was distilled at 111-115 !C at 0.5 mm/Hg to give a pale green solid. After recrystallization from benzene, there was obtained 2.8 g 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone as white crystals with a mp of 57-59 !C. This ketone has also been described as a pale-yellow oil with a bp of 115-118 !C at 0.4 mm/Hg. A solution of 0.7 g 1-(2,5-dimethoxyphenyl-4-methyl)-2-propanone in 20 mL MeOH was treated with 6.0 g ammonium acetate, 0.3 g sodium cyanoborohydride, and 3 g Linde 3 A molecular sieves. The mixture was stirred overnight, the solids removed by filtration, and the filtrate dissolved in 100 mL H2O. The solution was acidified with dilute H2SO4, and washed with 2x25 mL CH2Cl2. The aqueous phase was made basic with aqueous NaOH, and the product extracted with 2x25 mL CH2Cl2. The solvent was removed under vacuum, and the residue distilled (at 160 !C at 0.2 mm/Hg) to give colorless product which was dissolved in 3 mL IPA, neutralized with concentrated HCl, and diluted with 50 mL anhydrous Et2O. There was obtained 0.18 g of 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) as a white solid with a mp of 187-188 !C. The optical isomers of DOM have been prepared in two ways. The racemic base has been resolved as the ortho-nitrotartranilic acid salt by recrystallization from EtOH. The (+) acid provides the (+) or RSS isomer of DOM preferentially. Also, the above-mentioned 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively aminated with optically active alpha-methyl benzylamine with Raney Nickel. This amine is isolated and purified by recrystallization of the hydrochloride salt. When optically pure, the benzyl group was removed by hydrogenolysis with palladium on carbon. The mp of either of the optical isomers, as the hydrochloride salts, was 204-205 !C. DOSAGE: 3 - 10 mg. DURATION: 14 - 20 h. QUALITATIVE COMMENTS: (with 1.0 mg) There is almost certainly an effect. Physically there is a slight dryness in the mouth, and my eyes are noticeably dilated. There is an eerie feeling overall. (with 2.3 mg) Mood elevation at 2-3 hrs. After 3 hours, emotional effects become more pronounced, enhancement of color also. Very little distortion of perception, no disorientation, no creeping or flowing, but color enhancement considerable. The emotional content and empathy for others was closer to mescaline than to amphetamine, a welcome change. No suggestion of nausea at any time. Unable to sleep at ten hours, so I took 3/4 grain Seconal. Headache and listlessness next morning, probably due to the Seconal. (with 3 mg) In the middle of the experience I found that I was able to separate components of complex things so as to evaluate them separately. There is no need to respect their normal purpose. The sharpness of observation is enhanced, but one can focus at every different depth of a thing or a concept. Colors are not just brighter; there are more of them. There is a profoundness of meaning inherent in anything that moves. A line of thought or a bit of personal history ties the thinker to the objects that had been thought of, or once experienced. It is this relationship that will prove productive. Not like in a movie which is circular in its totalness, but as in true life where the future is the result of your own involvement with everything about you. (with 4 mg) The first four hours were largely directed to the body. There was a shuddering, and a tight jaw, and I am not particularly motivated to talk to anyone. It is more arousing (like amphetamine) than depressing (like phenobarb). I am feeling just a little sick at the three hour point, but a bit of regurgitation clears this up. Then at the fourth hour, it went totally outside of me. I saw the clouds towards the west. THE CLOUDS!!! No visual experience has ever been like this. The meaning of color has just changed completely, there are pulsations, and pastels are extremely pastel. And now the oranges are coming into play. It is a beautiful experience. Of all past joys, LSD, mescaline, cannabis, peyote, this ranks number one. Normally I have no color effects with mescaline. A dynamic experience. Feels good, too. (with 5 mg) There was the magnification of light, color and odors. It was all very pleasant and beautiful, except that I had an overwhelmingly negative feeling. This at times grew to considerable intensity, and I feel it was clearly due to anger. At times the negativity disappeared completely, and I broke into the most enjoyable, even hilarious experiences. I alternated about 50-50 between joy and discomfort. As the evening drew on, I became withdrawn and pensive. It seemed clear that I had made all the wrong decisions Q choice of partner, place to live, isolation, no meaningful activity. The greatest shocker was that my practice of meditation, which is one of my central focuses, and which I thought had brought me much peace and understanding, seemed to be a delusional solution to my unhappiness and isolation. The experience continued unabated throughout the night with much tension and discomfort. I was unable to get any sleep. I hallucinated quite freely during the night, but could stop them at will. While I never felt threatened, I felt I knew what it was like to look across the brink to insanity. (with 8 mg) The very quiet development picks up speed betweeen the first and second hour. There is a rich curly-imaged eyes-closed show that interlocks closely with music. It is occasionally an off-beat fantasy and not directly knit together, and even occasionally unenjoyable. But always intense and completely appropriate to the music. There is a continuous thirst, and little urine. Napping seems OK at 16 hours, but real sleep must wait until the 20 hour point. Overall a rolling +++, and I am looking forward to a repeat some day. (with 10 mg) If on this page I shall have expressed it to you then it is true that DOM has the glory and the doom sealed up in it. All that's needed to unseal it is to surround it with a warm living human for a few hours. For that human for those hours all the dark things are made clear. (with 12 mg) The first awareness was at 30 minutes and it was in the tummy. The development was extremely rapid, something more like LSD than previously remembered. The body tremor feels like poisoning, there is no escaping the feeling of being disabilitated, but at least there is no nausea. This transition ended and the trauma cleared completely at about the second hour. The music was exceptional, the erotic was exceptional, the fantasy was exceptional. Listz's RA Christmas Cantata #1,S part 1, with eyes closed was an experience without precedent. There were some residual effects still noted the next day. This may be a bit much for me. (with 0.3 mg of the RRS isomer) Maybe slightly wiry? No effects. (with 0.5 mg of the RRS isomer) There is a real effect, and it is significant that the first effects of the racemate were noted at 1.0 milligram. There is a trace of time slowing and in general a pretty full manic state. There is some mydriasis. Everything had pretty much cleared up by evening. (with 2.0 mg of theSSS isomer) No effects. There was an unexpected slight tachycardia at the two hour point, but nothing suggesting psychotropic action. (with 2.6 mg of the RSS isomer) There are signs of both pulse increase and blood pressure increase. There is some teeth-rubbiness, but still no psychological turn on at all. EXTENSIONS AND COMMENTARY: The rationale for the design and making of DOM has already been discussed. One could predict that it could have been, theoretically, a totally inactive compound and maybe an effective blocker for whatever receptor sites are being occupied by other psychoactive drugs and even for strange things that some unbalanced people might actually make within their bodies, using their own personal chemistry. On the other hand, it could have been a potent psychedelic in its own rights, and if so, probably long lived. The latter Rcould have beenS proved to be so. The very modest amount of study of the individual optical isomers clearly indicates that the RRS isomer is the more active. The sparse comments suggest that some of the heavier physical aspects of the racemate might be due to contributions from the RinactiveS RSS isomer. It is, after all, the RSS isomer of amphetamine that carries the major punch of that stimulant. Maybe if that isomer were removed, and one were to explore the pure RRS isomer of DOM, the dramatic visual aspects of the larger dosages might not be complicated with a troublesome physical component. This compound, unbeknownst to me, was scattered widely and plentifully in the heyday of the Haight-Ashbury in San Francisco, in mid-1967. It was distributed under the name STP, which was said to stand for Serenity, Tranquility, and Peace. It was also claimed to represent Super Terrific Psychedelic, or Stop The Police. The police called it: Too Stupid to Puke. Actually, the name was taken from the initials of a motor additive which was completely unrelated chemically. Incredibly, and sadly, one of the avowed experts in the area of the Rsensuous drugsS actually stated that STP, the motor oil additive, was really one and the same as STP, the highly dangerous psychedelic. The motor oil additive, he wrote in a book of his, had properties somewhat related to those of LSD, mescaline, and the amphetamines. How fortunate that the love children of the time didnUt do much reading, for they might have gotten into yet deeper pharmacological troubles with drug raids on the local gasoline stations. Two complications became apparent during this first appearance and they led to serious difficulties. One, there was no equation made between STP and DOM. No one knew what this drug was which had been distributed in a cavalier way throughout the city. There could be no educated guess as to the best treatment of overdose emergencies. And secondly, the initial tablets that had been distributed apparently contained 20 milligrams of DOM per tablet; later, it was dropped to 10 milligrams. Either of these, in retrospect, is now known to be a thoroughly whopping dose. The overdose situation was aggravated by the slow onset of DOM. The user may be aware of some initial effects at the half-hour point, there will be what might be called a + or ++ at the end of the first hour, and the full impact of the drug is not appreciated until some two hours have elapsed. But many of the recipients of the free handouts of DOM were familiar with LSD which can show its alert in 15 to 20 minutes, or even sooner with a large dose, and there is already a deep and compelling intoxication felt at the half-hour point. They, quite reasonably, expected this familiar activity pattern with STP and assumed, when there was little if any activity noted at the half-hour point, that the potency was less than expected. They took one or even two additional dosage units. Thus, some of the overdose victims of that period may well have taken as much as 30 mg of DOM. The slow onset of action, coupled with the remarkably long duration, caught many innocent users unprepared. Clinical studies have documented the rapid tolerance development from repeated exposures to DOM. Five volunteers were given 6 milligrams daily for three days. Objectively, psychological tests showed a decrease in responses. Subjectively, all found extremely intense effects on the first day, and all but one found it unpleasant. By the third exposure on the third day, all had diminished responses, ranging from only Rmoderately strongS to Rfelt absolutely nothing.S One actually slept during the experience on the third day. The hexadeutero-analogue (deuterium atoms on the two methoxyl groups) has been prepared as an internal standard for analytical work, but there are no reports of its human pharmacology. A study with this sort of derivative would be a fine companion to the studies already underway with the mescaline analogues that are similarly substituted. A difference exists, however. With mescaline, it is believed that the loss of a methoxyl group is a step towards the inactivation of the compound, whereas with DOM this loss may be associated with the formation of an active metabolite. The several fascinating questions raised by possible differences in both the rates and the degree of demethylation of these two compounds are well worth trying to answer. A number of compounds related to DOM had been synthesized and studied at the University of California at San Francisco, at about this time. Two of these were simply the juggling of the two methoxyl groups and the methyl group on the ring, still maintaining the 2,4,5-ness relative to the amphetamine chain. These are 2,4-dimethoxy-5-methylamphetamine and 4,5-dimethoxy-2-methylamphetamine. Since the slang name for DOM in and about the medical center was STP, and since STP was the name of a motor oil additive, it is not unreasonable that the first of these to be synthesized, the 2,4-dimethoxy-5-methyl isomer, was referred to by the name of another motor oil additive popular at that time, F-310. The Vilsmeier reaction between 2,4-dimethoxytoluene and the Vilsmeier complex of POCl3 and N-methylformanilide gave the benzaldehyde (mp 117-118 !C) with a yellow malononitrile derivative from EtOH with a mp of 193-194 !C. The nitrostyrene from this and nitroethane formed yellow crystals from CH3CN, with a mp 138-139 !C. The amine formed easily with LAH in ether, and the product F-310 (or 5-DOM) gave white crystals from CH3CN with a mp of 182-183 !C. And the other isomer, the 4,5-dimethoxy-2-methyl counterpart, became known familiarly as F-320, or sometimes simply 2-DOM. Its preparation followed an identical procedure, starting from 3,4-dimethoxytoluene. I have been told that F-310 is not active even at 20 milligrams in man, which would make it several times less potent than DOM (STP). I know of no trials with F-320. The use of the letter RFS does not imply any relationship between these two compounds and the series described elsewhere with the RFS code followed by other numbers, such as F-2 and F-22. These latter are F's because they are furans, not motor oil additives. And yet another oil additive, well known at the time as Z-7, became associated with the synthesis of the DOM (STP) isomer with its groups in the 2,4,6-positions. This is entered separately under y-DOM. #69 Y-DOM; Z-7; 2,6-DIMETHOXY-4-METHYLAMPHETAMINE SYNTHESIS: To a solution of 2,6-dimethoxy-4-methylbenzaldehyde (mp 92-93 !C from the lithiation of 3,5-dimethoxytoluene followed by reaction with N-methylformanilide) in 10 mL nitroethane, there was added 0.1 g anhydrous am-monium acetate and the mixture was heated on the steam bath for 16 h. Removal of the solvent under vacuum gave a slightly oily red-orange crystalline mass which was finely ground under 1 mL of MeOH. Filtration and a sparing wash with MeOH gave, after air drying, 0.8 g of a light yellow crystalline solid with a mp of 121-122.5 !C. Recrystallization from 4 mL boiling absolute EtOH gave 0.6 g of 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene as very light yellow platelets, which melted at 123-124 !C. To a solution of 0.25 g LAH in 25 mL refluxing THF, well stirred and under He, there was added a solution of 0.3 g 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene in 5 mL dry THF. Upon the completion of the addition, the reaction mixture was held at reflux for 48 h. After cooling with an external ice bath there was added, in sequence, 0.5 mL H2O, 0.5 mL 15% NaOH, and finally 1.5 mL H2O. The inorganic solids were removed by filtration, and the filter cake washed with THF. The solvent from the combined filtrate and washings was removed under vacuum, and the residue (0.3 g) was a crystal clear colorless oil with a high refractive index. This was dissolved in 2 mL IPA, neutralized with concentrated HCl, and diluted with 35 mL of anhydrous Et2O. After a minute's standing, the solution became turbid, followed by the slow deposition of very fine white crystals. After standing 1 h at room temperature, these were removed by filtration, Et2O washed, and air dried to constant weight. There was thus obtained 0.3 g 2,6-dimethoxy-4-methylamphetamine hydrochloride (y-DOM) with a mp of 203 !C. sharp. DOSAGE: 15 - 25 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 14 mg) I am really quite spacey. I can go from a train of thought straight up into thin air. Then, to get to another one there must be a careful choice of words. Logic has nothing to do with any of it. There is no trace of the MDMA-like magic. This is an interpretive drug, not simply an ASC [altered state of consciousness] opening. (with 18 mg) There is a light-headedness, and a somewhat starry-eyed stoned state. Nothing visual, and no body concern except for what seems to be a very fine inner tremor. I think that with a little more, things might very well begin to move in the visual field. But I have no feeling of great concern about taking a somewhat higher dosage. (with 25 mg) I was at a +++ for about three hours, and it was a very weird place. There were some visuals, but they were not at all commensurate with the degree to which I was simply stoned. The erotic does not knit, and it's hard to get involved with music. It is as if you were going down some totally unknown street in a completely familiar city. You know the territory, but yet it is strangely all new. Eyes closed fantasy and shaped imagery was quite remarkable. But some heart arrhythmias and a pretty constant diarrhea made the experience less than totally ideal. My sleep was good and with good dreams. EXTENSIONS AND COMMENTARY: I canUt remember the exact names of the companies that went with the oil additives. STP was, I believe, itUs own thing, and originally stood for Scientifically Treated Petroleum. And F-310 was, I believe, a Chevron Oil product. F-320 was, of course, the product of the wild and happy chemists at the Pharmaceutical Chemistry Department at the University of California in San Francisco, playing with what they fondly called Rfunny drugs.S And when the 2,4,6-orientation became an obvious positional isomer, the Pennzoil Oil Company's additive, Z-7, was a natural to have its name volunteered to the cause. There was one additional isomer possible, with the methyl in the 2-position and the methoxyl groups at the 4- and 6-positions. This followed the more conventional aldehyde made from 3,5-dimethoxytoluene via the Vilsmeier process, with POCl3 and N-methylformanilide. This material (2,4-dimethoxy-6-methylbenzaldehyde with mp 64-65 !C from cyclohexane or from MeOH) is completely distinct from the isomer used above (2,6-dimethoxy-4-methylbenzaldehyde with a mp of 92-93 !C from MeOH). The amphetamine from this isomer is 2,4-dimethoxy-6-methylamphetamine, and had been christened by the chemistry crowd as Z-7.1. Much effort had been put forth in research by this medical school group of graduate students and graduate advisors, to try to explain the biological activity of the 2,4,5-things such as TMA-2 and DOM (STP). And a considerable investment had been made in the attempt to tie together the amphetamine world of psychedelics with the indole world of psychedelics. The convenience of having two methoxy groups para to one another was a clear invitation to speculate upon the formation of a benzoquinone intermediate of some kind, and this would require the loss of the methyl groups which were already known to be metabolically labile. This Rquinone-likeS intermediate was the cornerstone of a Rhydroquinone hypothesis,S as it allowed further condensation within the molecule itself involving the primary amine group, to form something called an indolene which, with some arcane electron pushing and removal, could eventually become an indole. There. We now have a tie-in to the tryptamine world, and to serotonin, and that entire neurotransmitter magic. There was only one small fly in the ointment. No matter how the 2,4,5-things were explained, none of the proposed mechanisms could allow for the 2,4,6-things to also be active. How can one accommodate such blasphemy? The first and obvious approach was the simplest. Denial. The 2,4,6-things arenUt really active at all. Placebo stuff. There is a commonly used phrase, Rbad scienceS which is an in-famous term used to belittle findings that do not fit with one's theories or purposes. But that simply didnUt wash, because I knew, as did a few others who chose not to identify themselves too publicly, that TMA-2 and TMA-6 were both fully active in the 40 to 50 milligram area. And although not as potent as DOM, the compound of this recipe, y-DOM or Z-7, was certainly an active one. So, since approach number one didnUt work, try approach number two. Make the shoe fit the wearer, without respect to the size of his foot. One single size shoe fits all. One single mechanistic hypothesis explains all. It was obvious that for the RhydroquinoneS hypothesis to survive, Z-7 would have to undergo some metabolic oxidation Q phenol formation Q in the 3-position. And guess who was actually euchred into embarking onto the synthesis of this hypothetical metabolic Lucy [that's the anthropological-type, not the LSD-type Lucy]? Moi! On to a new methoxylated amphetamine which would be called Z-7.2. Oxidation of the above 2,4-dimethoxy-6-methylbenzaldehyde with metachloroperoxybenzoic acid gave 2,4-dimethoxy-6-methylphenol which smoothly methylated (KOH, CH3I) to give 2,3,5-trimethoxytoluene as a white oil, bp 59-62 !C at 0.1 mm/Hg. This formed the anion between the meta-methoxy groups with butyllithium, and N-methylformanilide gave the new compound 2,3,6-trimethoxy-4-methylbenzaldehyde, also an oil (bp 130-140 !C at 0.7 mm/Hg) with an excellent NMR spectrum. This formed the 3-carbon nitrostyrene with nitroethane, as bright yellow crystals from methanol with a mp 67-68.5 !C (and excellent NMR and microanalysis, C,H,N). Lithium aluminum hydride reduction gave rise to what I was assuming would be the target amphetamine, 4-methyl-2,3,6-trimethoxyamphetamine or Z-7.2. This formed a hydrochloride salt which, although analytically excellent, insisted in remaining as an ether and chloroform-soluble oil which had an excellent NMR spectrum. This was certainly MY target compound, but it was not THEIR target compound. The upper echelons who were running the show were serious about this hydroquinone thing. Therefore, this product Z-7.2, that should have been entered into human evaluation, was instead processed further by the substitution of a t-BOC on the amine group, oxidation to the quinone with ceric ammonium nitrate, reduction to the hydroquinone with dithionite, and finally deprotection of the blocking t-BOC group by hydrochloric acid. The final product, 2,5-dihydroxy-6-methoxy-4-methylamphetamine hydrochloride, was an extremely light-sensitive solid which was looked at by NMR (excellent spectrum in D2O) and by cyclic voltimetry (destructive and uninformative) but which would have been totally worthless to have tasted. In fact, the whole 2,4,6 substitution concept is just now beginning to explode. Fully half of the drugs described in this Book II are of the classical 2,4,5-trisubstitution pattern, and it is becoming evident that every one of them will have a 2,4,6-trisubstituted counterpart that bids fair to be an active psychedelic. Diligence could thus easily double the number of known psychedelics. The nickname RpseudoS is really the Greek letter RpsiS which looks like a candelabrum standing on the table holding up three candles. If I can find the type in some font, I will simply precede each known drug with this letter, to indicate that the 2,4,5-ness has become a 2,4,6-ness. Therefore, Z-7 is also pseudo-DOM. Z-7.2 might have been an interesting compound to taste. But the academic climate was not appropriate at that time (early 1977) for such honesty. The Rhydro-quinone hypothesisS is now not much more than a minor bit of history. And anyhow, it was just about this time that I had uncovered a slick way of getting a sulfur atom into the amphetamine molecule. I quickly lost interest in the pursuit of other people's hypotheses that didnUt seem to lead anywhere. Maybe, someday, some single earth-shaking mechanism will emerge to explain everything. But in the meantime, the best contribution I can make to this Rgrand unified theory of psychedelic activityS is to continue to make new and unexpected things which, if they are active, will effectively destroy any hypothesis that just happens to be popular at the moment. It is a lot more exciting, too. #70 DON; 2,5-DIMETHOXY-4-NITROAMPHETAMINE SYNTHESIS: A solution of 8.4 g 2,5-dimethoxyamphetamine base in 40 mL acetic acid was added dropwise over the course of 0.5 h to 43 mL of 50% nitric acid which was well stirred and cooled with an external ice bath. The resulting solution was quenched with ice water, made basic with aqueous NaOH, and extracted with a benzene-ether mixture. The residue that remained after the removal of the solvent was dissolved in dilute HCl which, upon evaporation of the H2O, yielded a nearly colorless residue. Recrystallization from an ethanol/ether mixture gave, after drying, 10.5 g of 2,5-dimethoxy-4-nitroamphetamine hydrochloride (DON) with a mp of 206-207 !C. The acetamide derivative melted at 166-168 !C. The formamide derivative was easily hydrolyzed with 3N HCl. And the R-isomer of DON hydrochloride had a mp of 231-232 !C. DOSAGE: 3.0 - 4.5 mg. DURATION: 8 - 15 h. QUALITATIVE COMMENTS: (with 3.0 mg) There was an amphetamine-like stimulation that was apparent an hour into it, and considerable anxiety. I had stomach cramps, but there were indications that there might be something hallucinogenic at a higher dose. (with 4.5 mg) An enhancement of color perception, and some auditory distortion, that was still noticeable some eight hours into the experience. The visual changes were intense. I felt I was running a slight fever, and was restless, but there was almost no physical malaise. I was still somewhat wound up even at the 14th hour. EXTENSIONS AND COMMENTARY: These qualitative comments are not true quotations, but have been reconstructed from the published summaries of the human trials reported by several South American researchers. I have personally never tasted DON and have only these fragments from which to create a portrait of activity. A brief quotation, from a note published by these researchers in a bulletin that is restricted to forensic scientists serving law enforcement agencies, is certainly subject to a number of interpretations. It reads as follows: RThis action [a strong stimulant action reminiscent of amphetamine] seems to reduce the incidence of insightful, and therefore potentially unpleasant experiences, and thus [DON seems likely] to appear on the market as an illicit recreational drug.S I must admit that I have tried, and I am still not able, to interpret this quotation. #71 DOPR; 2,5-DIMETHOXY-4-(n)-PROPYLAMPHETAMINE SYNTHESIS: A suspension of 285 g mossy zinc in 285 mL H2O containing 5.7 g mercuric chloride was treated with 285 mL concentrated HCl and shaken as needed to effect amalgamation. The H2O was then drained off, the zinc washed with fresh water and drained again. There was added a solution of 74 g 2,5-dimethoxypropiophenone (from the reaction of propionic acid and p-dimethoxybenzene in the presence of polyphosphoric acid, see under DOAM for an effective general procedure) in 140 g EtOH. The reaction mixture was held at reflux for 24 h with the periodic addition of concentrated HCl. It was then cooled, diluted with H2O and CH2Cl2, and the organic phase separated. The aqueous phase was extracted with 2x100 mL additional CH2Cl2. The combined organic phases were washed with 5% NaOH until the washes remained basic, once with H2O, and then the solvent was removed under vacuum. The residue was distilled at the water pump, giving an early fraction quite rich in starting p-dimethoxybenzene, and a second fraction (61 g, bp 140-160 !C) which was free of carbonyl group by infra-red, and which was largely 2,5-dimethoxypropylbenzene. It was used without further purification in the following aldehyde synthetic step. A mixture of 124 g N-methylformanilide and 140 g POCl3 was allowed to stand until there was the development of a strong red color. There was then added 60 g of the above 2,5-dimethoxypropylbenzene and the mixture was held on the steam bath for 2 h. The mixture was added to 2 L H2O and stirred until the excess acid chloride had completely decomposed. The mixture was extracted with 3x100 mL CH2Cl2 and, after the removal of the solvent from the combined extracts, the residue was extracted with 3x100 mL boiling hexane. Removal of the solvent gave the product 2,5-dimethoxy-4-propylbenzaldehyde as an oil, 23 g, which was characterized as its malononitrile derivative. Equal weights of the product and malononitrile in EtOH with a catalytic amount of triethylamine gave yellow crystals which, on recrystallization from toluene, had a mp of 113-114 !C. A solution of 21.5 g of the above crude 2,5-dimethoxy-4-propylbenzaldehyde in 75 g acetic acid, was treated with 10.4 g nitroethane and 6.6 g anhydrous ammonium acetate. This was heated on the steam bath for 1.75 h, then cooled and diluted with H2O to the point of turbidity. With long standing and scratching, there finally was the deposition of crystals which were removed by filtration and sucked as dry as possible. This 23 g of crude product cake was triturated under MeOH, filtered again, and air dried to give 11 g of dull orange crystals. Recrystallization from boiling MeOH gave 1-(2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene as fine orange crystals which weighed, after filtering, washing, and drying, 7.4 g, and which had a mp of 94-96 !C. To a suspension of 6.0 g LAH in 500 mL anhydrous Et2O, which was being stirred and also held as a gentle reflux, there was added a saturated solution of (2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene in warm THF. The reaction mixture was held at reflux for 24 h, then cooled to room temperature. The excess hydride was destroyed by the cautious addition of 500 mL dilute H2SO4. The phases were separated, and the aqueous phase washed with additional Et2O. There was then added 150 g potassium sodium tartrate, and the pH was brought to >9 with aqueous NaOH. The product was extracted with Et2O and, after removal of the solvent, the residue was dissolved in 200 mL anhydrous Et2O and saturated with anhydrous HCl gas. The solids that formed were removed by filtration, giving 6.15 g 2,5-dimethoxy-4-(n)-propylamphetamine hydrochloride (DOPR) as an electrostatic, white crystalline powder, with a mp of 182.5-183 !C. This was not improved by recrystallization from either IPA or CH3CN. DOSAGE: 2.5 - 5.0 mg. DURATION: 20 - 30 h. QUALITATIVE COMMENTS: (with 2.0 mg) The onset is slower than any other thing I can think of. There was nothing at all at the end of an hour, and only a threshold a half hour later. By the middle of the third hour, I was up to 1+, and that seemed to be about as high as it intended to take me. Attempts to sleep at the ninth hour were not successful, as there were strange patterns of not-quite logical thinking going on. Stuff like: TThe block events (like a babyUs rectangular building blocks) that were gotten, along with other things, from the full octaves of the left hand in Listz's Hungarian Rhapsody, events that allowed an easy recognition of the odds of achieving successful re-entry from any of several erotic codes.U Clearly this was not a baseline state. After six hours of successful sleep, I was still off-baseline , and on into the following day. Go on up with curiosity but with caution. (with 3.6 mg) Imagery that was constructed in response to the music turned out to be necessary to organize and contain it. The trio is the nucleus that transforms the written to the heard, but it has created its own bubble without connections to the real world, and must play on and on and on to keep itself afloat and never touching the stage again. (with 5.0 mg) I am now at midnight, and still strongly +++. This is certainly maximum dosage, at least for a long time. There are faint intimations of nervous system scrungies. You know, the kind of thing that makes you figure it's going to be a while before youUll try to relax into sleep. This material, like all the other DOUs, is a heavy duty psychedelic, the kind that says to you, 'Forget all that stuff about screening out visuals,' and then proceeds to prove it. Sort of indole-like in that way. Your body as well as your mind tells you youUre into it, baby, and better relax and enjoy the trip, because youUve left the shore way behind. When it was time for bed, I got to sleep with surprising ease, and slept for only about six hours. My dreams were excellent, balancing, and good humored. But the next day I realized I was still carrying the DOPR in me, and that baseline was definitely not there. But it was OK. No problems except for sleepiness. The next evening I went to bed at unheard-of hour of 9 PM and slept for 13 hours, give or take. Fascinating compound, but I wonUt go out of my way to take it again soon. EXTENSIONS AND COMMENTARY: There is a thread of disconnection and of inconsistent reference that pervades most of the reports that I have received concerning the use of DOPR. The word that comes to mind is hypnogogic. There is a drifting into that place that lies between a not-quite-awake and a not-quite-asleep state seems to characterize this compound. There is no question but that it is very potent, and that it is very long-lived. But there is a nagging suggestion of the out-of-body, out-of-center character that is the hallmark of the anesthetic and delusional drugs such as scopolamine or ketamine. With them, the psychedelic effects become clouded with touches of amnesia. If DOPR shows this with it's three carbon alkyl group, thereis every reason to pay close attention as the chain becomes longer. There had been quite a bit of speculation in the literature that the metabolic attack on DOM was at the 4-position, and this was an oxidation process. In a moment of inspiration, I decided to explore a similar oxidation step in DOPR, since it is probably the most potent of the DO-series. Why not make the compound which would be the first step in this oxidation, the 1-hydroxypropyl analogue? This I did, by using the phthalimide derivative of 2,5-dimethoxyamphetamine (described in the synthesis of DOI) and making the propiophenone using propionic acid as both reagent and solvent, and polyphosphoric acid as the condensing agent. The ketone product (a white crystalline solid from methanol) was dissolved in warm methanol and reduced to the alcohol with sodium borohydride. This product, also a white crystalline solid, was stripped of the phthalimide blocking group with overnight refluxing with hydrazine in ethanol. The product, 2,5-dimethoxy-4-(1-hydroxypropyl)-amphetamine (hydroxy-DOPR) had a mp of 148-150 !C from IPA. Its activity is not yet known, but there were no effects at all at trials, orally, of up to 200 micrograms. But this is all with the normal-propyl compound. There is a rich collection of misinformation and potential discovery that is associated with the isopropyl isomer. This structural isomer, 2,5-dimethoxyl-4-(i)-propylamphetamine is properly called DOIP for des-oxy-iso-propyl. It has been synthesized and explored in animals and, to a modest extent, in man. The synthesis has proceeded from 2,5-dimethoxyacetophenone by the addition of a methyl group to the carbonyl followed by reduction to the hydrocarbon. Aldehyde formation, nitropropene synthesis with nitroethane, and lithium aluminum hydride reduction are uneventful, providing the hydrochloride salt DOIP, which has a mp of 183-184 !C as an analytical sample. Animal tests (such as rabbit hyperthermia assays), have indicated that the isopropyl compound DOIP is less potent than the propyl prototype, DOPR, by between one and two orders of magnitude. In man, a dose of four milligrams, a rousing dose of DOPR, is without any effects. At 10 milligrams, there is some disturbance but substantially no effects. I have been told that with doses in the 20 to 30 milligram range there are valid changes in mental state, but I have not been told the nature of these changes. A fascinating red herring had been drawn across all of these exacting lines by a strange visitor to this research project. An olive-faced M.D., Ph.D., passed through this confusing scene briefly, and when he left, a small supply of DOPR left with him. He promptly published in an obscure journal some animal behavioral responses which he ascribed to the isopropyl analogue, DOIP. But what he had studied could only have been DOPR since DOIP, at that time, had not yet been synthesized either by me, or by either of the other two active synthesists of that moment. It was not yet a known material. We all made it some time later, but by that time our olive-face had disappeared. There is a magnificent French phrase that applies here as nowhere else; Il a foutu le camp. Its idiomatic meaning is equivalent to our, RHe took off,S or RHe split the scene,S but the literal translation is, RHe fucked the camp. #72 E; ESCALINE; 3,5-DIMETHOXY-4-ETHOXYPHENETHYLAMINE SYNTHESIS: To a solution of 72.3 g 2,6-dimethoxyphenol in 400 mL MeOH, there was added 53.3 g of a 40% solution of aqueous dimethylamine folowed by 40 g of a 40% aqueous solution of formaldehyde. The dark solution was heated under reflux for 1.5 h on a steambath. The volatiles were then removed under vacuum yielding a dark oily residue of 2,6-dimethoxy-4-dimethylaminomethylphenol. This residue was dissolved in 400 mL of IPA, to which there was added 50 mL of methyl iodide. The spontaneously exothermic reaction deposited crystals within 3 min, and was allowed to return to room temperature and occasionally stirred over the course of 4 h. The solids were removed by filtration, washed with cold IPA, and allowed to air dry yielding 160 g of the methiodide of 2,6-dimethoxy-4-dimethylaminomethylphenol as a cream-colored crystalline solid. A suspension of 155 g of the above methiodide of 2,6-dimethoxy-4-dimethylaminophenol in 600 mL H2O was treated with a solution of 130 g KCN in 300 mL H2O. The reaction mixture was heated on a steam bath for 6 h during which time there was a complete dissolving, the development of a brownish color with a bright blue film on the surface and the walls of the flask, and the gentle evolution of fine gas bubbles. The hot reaction mixture was poured into 1.2 L H2O and acidified with concentrated HCl (careful, HCN evolution). The aqueous solution was extracted with 3x150 mL CH2Cl2, the extracts pooled, washed with saturated NaHCO3 which removed much of the color. The solvent was removed under vacuum yielding about 70 g of a viscous black oil. This was distilled at 0.4 mm/Hg at 150-160 !C to provide 52.4 g of homosyringonitrile (3,5-dimethoxy-4-hydroxyphenylacetonitrile) as a white oil that spontaneously crystallized to lustrous white crystals that melted at 57-58 !C. A solution of 5.75 g of homosyringonitrile and 12.1 g ethyl iodide in 50 mL dry acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and held at reflux for 18 h. The mixture was diluted with 100 mL Et2O, filtered, and the filtrate solvent removed under vacuum The residue was recrystallized from Et2O/hexane to yield 5.7 g 3,5-dimethoxy-4-ethoxyphenylacetonitrile with a mp 57-58 !C. Anal. (C12H15NO3) C,H,N. A solution of 2.21 g 3,5-dimethoxy-4-ethoxyphenylacetonitrile in 25 mL EtOH containing 2.5 mL concentrated HCl and 400 mg 10% palladium on charcoal, was shaken in a 50 lb/sq.in. atmosphere of hydrogen for 24 h. Celite was added to the reaction suspension and, following filtration, the solvents were removed under vacuum. The residue was recrystallized from IPA/Et2O to yield 2.14 g 3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) with a mp of 166-167 !C. Synthesis from syringaldehyde: A well-stirred suspension of 21.9 g syringaldehyde in 45 mL H2O was heated to reflux in a heating mantle. There was then added a solution of 15 g NaOH in 60 mL H2O. The heating and stirring was continued until the generated solids redissolved. Over a period of 10 min, there was added 23 g diethyl sulfate, then refluxing was continued for 1 h. Four additional portions each of 5 g diethyl sulfate and of 6 mL 20% NaOH were alternately added to the boiling solution over the course of 2 h. The cooled reaction mixture was extracted with Et2O, the extracts pooled and dried over anhydrous MgSO4, decolorized with Norite, and stripped of solvent. The crude 3,5-dimethoxy-4-ethoxy-benzaldehyde weighed 21.8 g and melted at 51-52 !C. A solution of 14.7 g 3,5-dimethoxy-4-ethoxybenzaldehyde and 7.2 mL nitromethane in 50 mL glacial acetic acid was treated with 4.4 g anhydrous am-monium acetate and held at reflux for 30 min. Cooling the reaction allowed the formation of yellow crystals which were removed by filtration and washed sparingly with cold acetic acid. The dried 3,5-dimethoxy-4-ethoxy-'-nitrostyrene weighed 11.5 g and melted at 108-109 !C after recrystallization from EtOH Anal. (C12H15NO5) C,H. Alternately, this product may be prepared from 3.9 g. 3,5-dimethoxy-4-ethoxybenzaldehyde in 60 mL nitromethane containing 0.7 g ammonium acetate and heated on a steam bath for 1 h. The solvent was removed under vacuum, and the residue dissolved in a minimum of hot MeOH. Cooling provided, after filtration and air drying, 2.3 g of bright yellow crystals of 3,5-dimethoxy-4-ethoxy-'-nitrostyrene, with a mp of 105-107 !C. A solution of 2.25 g LAH in 45 mL anhydrous THF was vigorously stirred and cooled to 0 !C under He. There was added 1.5 mL 100% H2SO4 dropwise, followed by 2.3 g 3,5-dimethoxy-4-ethoxy-'-nitrostyrene in anhydrous THF. After the addition was complete, the mixture was allowed to stir for 30 min, and then brought to room temperature. The unreacted hydride was decomposed with 2.3 mL H2O in THF, followed by the addition of 9.2 mL of 15% NaOH. The white suspension was filtered, the filter cake was washed with THF, the filtrate and washings combined, and the solvent removed under vacuum. The residue was dissolved in 300 mL dilute H2SO4, washed with 2x75 mL CH2Cl2, made basic with 25% NaOH, and the product extracted with 3x75 mL CH2Cl2. After removal of the solvent, the residue was distilled at 110-120 !C at 0.3 mm/Hg yielding 1.4 g of a colorless oil. A solution of this oil in 20 mL IPA was neutralized with 17 drops of concentrated HCl and diluted with 100 mL anhydrous Et2O. After a few minutes there was the spontaneous formation of white crystals of 3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) which was recrystallized from 40 mL boiling EtOAc containing 1 mL MeOH. The mp was 165-166 !C. DOSAGE: 40 - 60 mg. DURATION: 8 - 12 h. QUALITATIVE COMMENTS: (with 40 mg) This is a powerful and complex intoxicant Q I could not have coordinated any rational muscular activity. I could not walk; I could not tie my shoe-laces. There is analgesia and an incoordination that I cannot shake. My menstrual flow started a bit ahead of time, but it was light. (with 50 mg) I felt that the body tensions outweighed the psychological and sensory rewards, in that I had a lot of dehydration and my sleep had a nightmare quality. This pretty much offset the few virtues that I felt I had obtained. (with 60 mg) There is a quality of rational analysis and insight that is totally impressive. Many subtle factors in my life can be viewed with insight, and usefully dissected. I got into a deep discussion, but I was not argumentative or even defensive and I remained detached and kept a tone of cool impersonality. I had a good appetite. But I also had some tachycardia and muscular tension. There was unquestionable sensory enhancement, but without an intellectual component. Overall it was most pleasant. EXTENSIONS AND COMMENTARY: In an isolated situation, there is easy fantasy, but little synthesis of external sensory inputs such as music or visual stimulae. A gradual decline brings the subject back to a restful baseline somewhere before the 12th hour. The following day is often seen as one of tiredness and low energy. An anonymous flyer appeared in the California drug community in 1984 stating an effective range to be 50 to 100 milligrams, but it described the drug as the sulfate. The above data all pertain to the hydrochloride salt. The replacement of that one methyl group with an ethyl group leads to a nice jeu de mots. The play on words depends on a remarkable coincidence. The name of the alkaloid mescaline stems from an ancient Nahuatl word for a drink (Mexcalli) which also provided the source of the term Mescal (an Agave of entirely different pharmacology). The prefix for the simplest, the one carbon organic radical, is methyl. This is from the Greek word RmethyS and represents wine from wood. Such is, indeed, methyl alcohol, or methanol, or wood alcohol, the simplest one-carbon drink and a rather dangerous one for the human animal. And this is the group that is on the central oxygen of mescaline. It is customary to refer to homologs (bigger-by-one) of methanol by their classical chemical names, so the natural extension of methyl is ethyl, and that of mescaline would be escaline. One carbon-chain on the 4-position oxygen becoming a two-carbon chain. This is all entymologically appealing, but there is no botanical support for any of it. The ethyl group is much more rare in nature. It is just a happy coincidence that mescaline (the plant), and methyl (the alkyl group involved), and methoxy (the group on the 4-position of the aromatic ring) all happen to start with the letter RMS. Very few of the homomescaline phenethylamines have been synthesized as their three-carbon chain counterparts, the corresponding analogues of amphetamine. And only three of them have been explored in man (four, if you count the amphetamine analogue of mescaline itself, TMA). The obvious names for these compounds have, unfortunately, already been used. It would be logical to use the letter M for a methoxy, and the letter E for ethoxy, etc. and simply read the groups from around the ring. But this is the naming system for the 2,4,5-trisubstituted amphetamines. MEM is, for example, 2,5-dimethoxy-4-ethoxyamphetamine (in sequence, methoxy, ethoxy, methoxy reading around the ring, and a fascinating compound talked about at length in this book), so this term cannot represent 3,5-dimethoxy-4-ethoxyamphetamine. A truly simple code employs the length of the carbon chain. The phenethylamine chain is two carbons long, and the amphetamine chain is three carbons long. If a drug has been initially developed (and initially named) as an amphetamine derivative (three carbon chain) then the two-carbon chain analogue will use the original name (or a symbolic part of it) with the term 2C ahead of it. The two-carbon analogue of DOB (a three-carbon chain compound) will become 2C-B. DOI becomes 2C-I, DON becomes 2C-N, and DOET becomes 2C-E. Each of these is a substituted amphetamine derivative lacking one carbon atom, thus becoming a phenethylamine derivative. Most of these have 2,4,5-substitution patterns. And if a drug has been initially developed (and initially named) as a phenethylamine derivative (two carbon chain) then the three-carbon chain analogue will use the original name with the term 3C ahead of it. The three carbon analogue of E (escaline, a two-carbon chain compound) will become 3C-E. P becomes 3C-P and CPM becomes 3C-CPM. Most of these have 3,4,5-substitution patterns. Thus, R2-CS implies that a known amphetamine drug has been shortened to a phenethylamine, and R3-CS inplies that a known phenethylamine has been lengthened to an amphetamine. A great number of the former have been made and have proven to be most rewarding. Only a few of the latter are known, but most of them will eventually prove to be potent psychedelics. #73 EEE; 2,4,5-TRIETHOXYAMPHETAMINE SYNTHESIS: A solution of 13.3 g 3,4-diethoxyphenol (see the recipe for MEE for its preparation) in 20 mL MeOH, and a solution of 4.8 g KOH in 100 mL hot MeOH were combined. There was added 8.2 g ethyl bromide and the mixture was held at reflux on the steam bath for 2 h. The reaction was quenched by the addition of three volumes H2O, made strongly basic by the addition of 10% NaOH, and extracted with 3x150 mL CH2Cl2. The solvent was removed from the pooled extracts under vacuum giving a residue of 9.1 g 1,2,4-triethoxybenzene that solidified to a crystalline mass. The mp was 28.5-29.5 !C, but the infra-red analysis showed the presence of unreacted phenol. The CH2Cl2 solution was again washed thoroughly with 10% NaOH and, after removal of the solvent, the solidified residue weighed 6.0 g and appeared free of impurities. The mp of this sample was 33-34 !C. To a mixture of 10.5 g N-methyl formanilide and 11.9 g POCl3 that had incubated at room temperature for 0.5 h (it had become quite red in color) there was added 6.4 g of the solid ether, 1,2,4-triethoxybenzene. The mixture was heated on the steam bath for 2.5 h, then poured into 500 mL of shaved ice. After a few minutes stirring, crystals appeared. The reaction was allowed to stand for a few h, then filtered and sucked as dry as possible. The damp 14.4 g of slate-green crude solids were dissolved in 30 mL boiling MeOH, and allowed to cool to room temperature overnight. Filtration of the cream-colored product, and air drying, gave 6.1 g of 2,4,5-triethoxybenzaldehyde with a mp of 94-95 !C. A solution containing 0.5 g of this aldehyde and 0.4 g malononitrile in 7 mL absolute EtOH was treated with three drops of triethylamine. There was an immediate formation of granular yellow crystals of 2,4,5-triethoxybenzalmalononitrile which, on filtering and air drying, weighed 0.4 g and had a mp of 169-170 !C. A solution of 5.0 g 2,4,5-triethoxybenzaldehyde and 2.6 g nitroethane in 14.8 g glacial acetic acid was treated with 1.6 g anhydrous ammonium acetate and heated on the steam bath for 2 h. The addition of an equal volume of H2O gave a slightly turbid solution which, upon the administration of a small amount of externally developed seed, smoothly set up as orange crystals as the reaction mix returned to room temperature. The product was removed by filtration, washed with a little 50% acetic acid, and allowed to air dry to constant weight. There was thus obtained 2.5 g of fluffy yellow-orange (almost yellow) crystals of 2-nitro-1-(2,4,5-triethoxyphenyl)propene with a mp of 91-92.5 !C. Anal. (C15H21NO5) C,H. To a gently refluxing suspension of 1.7 g LAH in 200 mL anhydrous Et2O under a He atmosphere, there was added 2.5 g 2-nitro-1-(2,4,5-triethoxyphenyl)propene by allowing the condensing Et2O to drip into a shunted Soxhlet thimble containing the nitrostyrene, thus effectively adding a warm saturated solution of the nitrostyrene dropwise. Refluxing was maintained for 5 h, and then the reaction mixture was cooled with an external ice bath. The excess hydride was destroyed by the cautious addition of 300 mL 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 50 g of potassium sodium tartrate were dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was above 9, and this was extracted with 3x200 mL CH2Cl2. Removal of the solvent under vacuum produced an amber oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. After a few min delay, there com-menced the separation of fine white crystals of 2,4,5-triethoxyamphetamine hydro-chloride, (EEE). These weighed, after filtration, Et2O washing, and air drying to constant weight, 1.75 g and had a mp of 167-168 !C, with prior softening at 162 !C. Anal. (C15H26ClNO3) C,H,N. DOSAGE: unknown. DURATION: unknown. EXTENSIONS AND COMMENTARY: This amphetamine, the final item on the ethoxy homologue of TMA-2 project, has never been tried in man. I do not know how it tastes, but I suspect that it is probably bitter. An interesting sidelight concerning this project, and one which can serve as a measure of the enthusiasm that went into it, is that (except for the 2-ethoxy homologue EMM) all of the possible ethoxy homologues of TMA-2, including MEM, MME, EEM, EME, MEE and EEE, their precursor nitrostyrenes, the precursor aldehydes (and their malononitrile derivatives), the precursor ethers, and the precursor phenols, for a total of 33 compounds, were all synthesized, purified, and characterized within a period of just over three weeks. Actually it was 23 days, and that was a magically exciting time. And there were two true treasures that came out of it all. The compound MEM, and the knowledge that the 4-position was where the action is. #74 EEM; 2,4-DIETHOXY-5-METHOXYAMPHETAMINE SYNTHESIS: To a solution of 12.3 g 3-ethoxy-4-methoxyphenol (see recipe for MEM for the preparation of this phenol) in 20 mL MeOH, there was added a warm solution of 4.8 g KOH in 100 mL MeOH. There was then added 8.2 g ethyl bromide, and the mixture held at reflux on the steam bath. Within 0.5 h, severe bumping ensued. An additional 3 g ethyl bromide were added, refluxing continued for another 0.5 h, then the reaction mixture was allowed to come to room temperature and to stand overnight. It was poured into 3 volumes H2O which produced crystals spontaneously. There was added additional base, and the mixture was extracted with 3x150 mL CH2Cl2. Removal of the solvent from the pooled extracts under vacuum gave 6.4 g of 2,4-diethoxyanisole as tan crystals with a mp of 48-48.5 !C. A mixture of 10.9 g N-methylformanilide and 12.3 g POCl3 was allowed to stand at room temperature for 0.5 h producing a deep red claret color. There was then added 6.2 g 2,4-diethoxyanisole and the mixture was heated on the steam bath for 2 h. All was poured into 200 g chipped ice, and stirred mechanically. The dark viscous gummy oil gradually became increasingly granular and finally appeared as jade-green solids. These were removed by filtration and washed with H2O, giving a wet cake weighing 18 g and having a mp (from a porous plate) of 95.5-96.5 !C. The entire crop was recrystallized from 75 mL boiling MeOH which gave, after filtering, washing lightly with cold MeOH, and air drying, 5.4 g of 2,4-diethoxy-5-methoxybenzaldehyde with a mp of 98-99 !C. A solution of 0.2 g of this aldehyde, and 0.3 g malononitrile in 2.0 mL warm EtOH was treated with a drop of triethyl-amine. There was an immediate generation of crystals which were removed by filtration, EtOH-washed, and dried to constant weight. The bright yellow needles of 2,4-diethoxy-5-methoxybenzalmalononitrile weighed 0.15 g and had a mp of 172-172.5 !C. A solution of 5.0 g 2,4-diethoxy-5-methoxybenzaldehyde in 16 g glacial acetic acid was treated with 2.7 g nitroethane followed by 1.7 g anhydrous ammonium acetate. The mixture was heated for 2.5 h on the steam bath, then removed and diluted with a equal volume of H2O. With cooling there was the generation of a heavy crop of orange crystals which was removed, washed with 50% acetic acid, and sucked as dry as possible. The product had a mp of 97-104 !C, and there was spectrographic evidence of some unreacted starting aldehyde. A small sample was recrystallized from boiling MeOH, with considerable loss, to give an analytical sample of 1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene as orange-yellow crystals with a mp of 112-113 !C. Anal. (C14H19NO5) C,H. The unpurified first crop was employed in the following synthesis of the corresponding amphetamine. To a gently refluxing suspension of 2.9 g LAH in 400 mL anhydrous Et2O under a He atmosphere, there was added 4.0 g of impure 1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene by allowing the condensing ether to drip into a shunted Soxhlet thimble apparatus containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise over the course of 1 h. Refluxing was maintained for 5 h and the reaction mixture was cooled with an external ice bath with the stirring continued. The excess hydride was destroyed by the cautious addition of 400 mL of 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 100 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was above 9, and this was then extracted with 3x150 mL CH2Cl2. Removal of the solvent under vacuum produced 2.7 g of a pale amber oil that was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. After a few minutes delay, there commenced the separation of fine white crystals of 2,4-diethoxy-5-methoxyamphetamine hydrochloride (EEM). After the crystallization was complete, these were removed by filtration, washed with Et2O and air dried, providing 2.55 g of a fine white crystalline solid with mp 158-159 !C. Anal. (C14H24ClNO3) C,H,N. DOSAGE: unknown. DURATION: unknown. EXTENSIONS AND COMMENTARY: This particular identity and arrangement of the alkoxy groups on the amphetamine molecule, EEM, is a totally unexplored molecule. It is reasonable to assume that it would be way down in potency, but there is no way of guessing what the nature of its activity might be at the dosage that would be active. #75 EME; 2,5-DIETHOXY-4-METHOXYAMPHETAMINE SYNTHESIS: To a solution of 14.0 g 4-ethoxy-3-methoxyphenol (see the recipe for MME for the preparation of this starting material) in an equal volume of EtOH, there was added a solution of 5.3 g KOH in 100 mL hot MeOH. This was followed with 9.1 g ethyl bromide, and the mixture was held at reflux for 2 h. The first deposition of KBr was apparent in 5 min, and there was rather severe bumping by the end of the reaction. The mixture was diluted with 3 volumes H2O and 1 volume 5% NaOH, and extracted with 2x200 mL Et2O. The extracts were pooled, and the solvent removed under vacuum, yielding 14.3 g of a pale amber oil that set to crystals of 2,5-diethoxyanisole with a mp of 44-45 !C. The compound had been reported in the literature from the action of diethyl sulfate on methoxyhydroquinone. To a mixture of 24.1 g N-methylformanilide and 27.3 g POCl3 that had been allowed to stand at room temperature until strongly red-colored (about 0.5 h) there was added 13.8 g solid 2,5-diethoxyanisole and the mixture was heated on the steam bath for 2 h. The black, thick reaction product was poured over chipped ice and, with continuous stirring, the color lightened and there was the formation of a yellowish powder. After a few h standing, this was removed by filtration and sucked as dry as possible. The 32 g of damp product showed the presence of isomeric contaminatiion by GC, and the aqueous mother liquor, upon extraction with CH2Cl2 and concentration, showed yet more aldehyde-like impurities. The isolated solids were recrystallized from 125 mL boiling MeOH giving 15.8 g yellowish crystals (wet weight) that still showed detectable impurities by GC. A second recrystallization from 100 mL boiling MeOH gave off-white fluffy crystals of 2,5-diethoxy-4-methoxybenzaldehyde which weighed, after air drying, 8.5 g. The mp was 109-110 !C. The combined mother liquors from the two MeOH crystallizations were stripped of solvent, and the resulting solid mass crystallized again from MeOH to give a second crop of aldehyde, 5.7 g, with a mp of 110-111 !C. A solution of 1.0 g of this aldehyde and 0.7 g malononitrile in 40 mL warm absolute EtOH was treated with a few drops of triethylamine. In a minute or so, there was the formation of crystals. These were removed by filtration, washed with EtOH, and air dried, giving 0.6 g of 2,5-diethoxy-4-methoxybenzalmalononitrile as brilliant yellow crystals with a mp of 156.5-158 !C. A solution of 6.7 g 2,5-diethoxy-4-methoxybenzaldehyde in 21 g glacial acetic acid was treated with 3.1 g nitroethane and 1.93 g anhydrous ammonium acetate, and heated on the steam bath for 2.5 h. The addition of a small amount of H2O to the hot reaction mixture instituted crystallization of an orange product which, after the mixture had come to room temperature and stood for several h, was removed by filtration, H2O washed, and air dried. The product, 1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene, was dull orange in color, weighed 3.0 g and had a mp of 84-86 !C. An analytical sample from toluene had a mp of 85-86 !C. Anal. (C14H19NO5) C,H. To a gently refluxing suspension of 2.0 g LAH in 250 mL anhydrous Et2O under a He atmosphere, there was added 2.8 g 1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene by allowing the condensing Et2O to drip into a shunted Soxhlet thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise. The addition took 1 h and the refluxing was continued for an additional 6 h. The reaction mixture was brought down to ice-bath temperature, and the excess hydride was destroyed by the cautious addition of 150 mL 1.5 N H2SO4. When the aqueous and Et2O layers were finally clear, they were separated and 50 g of potassium sodium tartrate were dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3x150 mL CH2Cl2. Removal of the solvent under vacuum produced 2.3 g of a clear white oil that was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. At first the solution remained completely clear, and finally there was the start of the formation of fine white crystals. When the crystallization was complete, these solids were removed by filtration, Et2O washed, and air dried. There was thus obtained 2.2 g of 2,5-diethoxy-4-methoxyamphetamine hydrochloride (EME) with a mp of 162-164 !C with prior softening at 154 !C. Anal. (C14H24ClNO3) C,H,N. DOSAGE: unknown. DURATION: unknown. EXTENSIONS AND COMMENTARY: This is another of the collection of all possible ethoxy homologues of TMA-2. The latter and heavier members of this series were synthesized and completed before the directions of biological activity had become evident from the earlier ones. This compound has never been assayed, and it is a reasonable guess that it will have a very low potency, with hints of toxicity at higher dose levels. I suspect that it will never be assayed, certainly not by me. #76 EMM; 4,5-DIMETHOXY-2-ETHOXYAMPHETAMINE SYNTHESIS: A solution of 166 g 3,4-dimethoxybenzaldehyde in 600 mL acetic acid was well stirred, and brought up to an internal temperature of exactly 25 !C. There was added, in very small portions, a 40% solution of peracetic acid in acetic acid. The evolved heat was removed with an external ice bath, and the rate of addition was dictated by the requirement that the internal temperature should not exceed 25 !C. A total of 210 g of the 40% peracetic acid was used. The reaction mixture was poured into 3 L H2O, and the acetic acid neutralized by the addition of solid K2CO3. The neutral aqueousphase was extracted with 5x150 mL Et2O, and the solvent from the pooled extracts was removed under vacuum. To the red-colored residue there was added 300 mL 10% NaOH, and the mixture was heated for 1 h on the steam bath. This was cooled, washed once with CH2Cl2, acidified with HCl, and extracted with 5x150 mL Et2O. The pooled extracts were washed once with saturated NaHCO3 (which removed most of the color) and the removal of the solvent under vacuum gave 105 g of 3,4-dimethoxyphenol as an amber oil that slowly set up to crystals. The above crude 3,4-dimethoxyphenol was dissolved in 200 mL EtOH, and treated with a solution of 38.1 g KOH in 300 mL hot EtOH. The clear solution of the potassium salt was a deep red color, and was promptly treated with 94.3 g allyl bromide, at a rate commensurate with the exothermic reaction. The mixture was held at reflux for 2 h. This was then added to 1 L H2O and extracted with 5x100 mL Et2O. The extracts were pooled, and removal of the solvent under vacuum gave a residue of 98 g of a black oil. This was distilled at 104-108 !C at 0.7-1.0 mm/Hg to give 59.3 g 1-allyloxy-3,4-dimethoxybenzene as a pale yellow oil with a greenish cast. A total of 59 g of the neat 1-allyloxy-3,4-dimethoxybenzene was provided with an internal thermometer, and heated with an open flame. The color quickly became purple, then lightened to a red at 70 !C, and finally to a pale pink by 210 !C. At 240 !C an exothermic reaction set in with the temperature going up to almost 290 !C. It was held in the 270-280 !C range for several min, then allowed to return to room temperature. GC analysis showed two peaks, the second and major one being the desired 1,2,4,5-isomer. A small sample was caught by prep-GC, and it successfully seeded the crude Claissen rearrangement product. The isolated 2-allyl-4,5-dimethoxyphenol, pressed on a porous plate, had a mp of 39.5-40.5 !C which was improved to 41.5-42 !C by recrystallization from hexane. To a solution of 9.7 g 2-allyl-4,5-dimethoxyphenol in a few mL EtOH, there was added a solution of 2.8 g KOH in 25 mL boiling EtOH followed by 5.5 g ethyl bromide. The mixture was held at reflux for 3.5 h and then poured into 200 mL H2O and extracted with 3x100 mL CH2Cl2. Pooling the extracts and removal of the solvent under vacuum gave a residue of 10.4 g of 4,5-dimethoxy-2-ethoxy-1-allylbenzene as a clear, mobile oil. It was substantially a single component by GC and was used in the following isomerization step without further purification. A solution of 9.4 g 4,5-dimethoxy-2-ethoxy-1-allylbenzene in 10 mL EtOH was treated with 20 g flaked KOH, and heated on the steam bath. The progress of the isomerization was followed by the assay of isolates by GC. After 5 h, the reaction mixture was poured into 250 mL H2O which immediately generated a pasty solid. This was sucked free of solvent and other liquids on a sintered funnel, giving 5.5 g of trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene as an amber solid with a mp of 65-67 !C. A small analytical sample from hexane had a mp of 68 !C. A solution of 5.0 g trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene in 27 g acetone that contained 2.2 g pyridine was magnetically stirred and cooled to 0 !C. There was then added 4.5 g tetranitromethane and, after 2 minutes stirring at this temperature, the reaction mixture was quenched with a solution of 1.5 g KOH in 26 mL H2O. The reaction mixture remained a clear deep orange color, and additional H2O was required to institute crystallization. There was the slow deposition of bright yellow crystals of 1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitro-propene which weighed, after EtOH washing and air drying to constant weight of 4.4 g. The mp was 75-76 !C. To a gently refluxing suspension of 3.5 g LAH in 250 mL anhydrous Et2O under a He atmosphere, there was added 3.9 g 1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitropropene by allowing the condensing Et2O to drip into a shunted Soxhlet apparatus with the thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise; the nitrostyrene was very soluble in Et2O. Refluxing was maintained for 2.5 h and the reaction continued to stir at room temperature for an additional 3.5 h. The excess hydride was destroyed by the cautious addition of 225 mL 1.5 N H2SO4. When the aqeous and Et2O layers were finally clear, they were separated, and 75 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was then extracted with 3x100 mL CH2Cl2. Evaporation of the solvent under vacuum produced 2.8 g of a clear, almost colorless oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. This initially generated a solid that then oiled out. After a few minutes stirring, this began to solidify again and it finally transformed into a loose fine white solid. This was recrystallized by dissolution in 50 mL warm IPA followed by dilution with 300 mL Et2O. After a few minutes, crystals of 4,5-dimethoxy-2-ethoxyamphetamine hydrochloride (EMM) formed which were removed by filtration, Et2O washed, and air dried. These weighed 2.7 g and had a mp of 171-172 !C. Anal. (C13H22ClNO3) C,H,N. DOSAGE: greater than 50 mg. DURATION: unknown. QUALITATIVE COMMENTS: (with 50 mg) There were no effects. EXTENSIONS AND COMMENTARY: This was the first of the ethoxy homologues of TMA-2, and it was immediately (well, within a couple of months) run up from an initial dab to 25 milligrams. This was in early 1963, and the lack of activity of EMM was keenly disappointing. This was a level at which the prototype, TMA-2, was very active, and the conclusion was that maybe any change on the molecule would result in a loss of activity. So this approach was shelved for a while, and all efforts were directed into the relocation, rather than the elongation, of the methoxy groups. A few months later, the ethoxy question was addressed again, and the discovery of MEM rekindled full interest in this ethoxy question. #77 ETHYL-J; 2-ETHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE; N-ETHYL-1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE SYNTHESIS: A stirred solution of 9.0 g 1-(3,4-methylenedioxyphenyl)-2-butanone (see the recipe for J for its preparation) in 150 mL MeOH was treated with 9.0 g ethylamine hydrochloride, 4.0 g anhydrous NaOAc, and 3.0 g sodium cyanoborohydride. The pH was maintained between 6 and 7 by the periodic addition of HCl. After the base formation had stabilized, there was added an additional 9.0 g ethylamine hydrochloride, 9.0 g NaOAc and 2.0 g sodium cyanoborohydride. With continuous stirring, there was HCl added over the course of 1 h until the final pH was approximately 2. The reaction mixture was poured into 700 mL dilute NaOH, and extracted with 3x75 mL CH2Cl2. These extracts were pooled, and back-extracted with dilute H2SO4. This was washed with 2x50 mL CH2Cl2, then made basic with dilute NaOH and extracted with 2x75 mL CH2Cl2. Removal of the solvent under vacuum gave a 0.81 g residue which was dissolved in 10 mL IPA. Neutralization with concntrated HCl formed white crystals spontaneously. These were diluted with Et2O, filtered, Et2O washed and air dried to provide 0.85 g 2-ethylamino-1-(3,4-methylenedioxy-phenyl)butane hydrochloride (ETHYL-J), with mp of 176-177 !C. Anal. (C13H20ClNO2) C,H. The neutral fraction that remained in the organic phase following the dilute sulfuric acid extraction, was recovered by removal of the solvent under vacuum. There was obtained about 5 g of an amber liquid that was largely 2-hydroxy-1-(3,4-methylenedioxyphenyl)butane. DOSAGE: greater than 90 mg. DURATION: probably short. QUALITATIVE COMMENTS: (with 65 mg) Perhaps aware at 20 minutes. Definitely aware at 45 minutes. Diffusing to nothing at 3-4 hours. (with 90 mg) I am somewhere between 1 and +. And everything became lost in the evening with a couple of glasses of wine and talk that went on to 3 AM. EXTENSIONS AND COMMENTARY: And nothing higher has ever been looked at. If the analogy with the amphetamine counterparts (J with MDA, METHYL-J with MDMA, and this, with MDE) were to hold up (a drop of about a third in potency with the lengthening of the chain by a carbon atom), one might guess that this compound would be an interesting intoxicant, but probably not until you got up into the area at or above a 200 milligram dose. And that is a lot of chemical for the body to have to handle. Some day, maybe. #78 ETHYL-K; 2-ETHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)PENTANE; N-ETHYL-1-(1,3-BENZODIOXOL-5-YL)-2-PENTYLAMINE SYNTHESIS: A solution of 120 mg mercuric chloride in 160 mL H2O was poured over 4.7 g aluminum foil (Reynolds Wrap, regular weight, cut into 1 inch squares) and allowed to stand until the amalgamation was well underway (about 30 min). The H2O was then drained and the foil washed with 2x200 mL H2O with thorough draining. There was then added, in sequence and with good swirling and agitation between each addition, 8.5 g ethylamine hydrochloride dissolved in 7 mL H2O, 21 mL IPA, 17 mL 25% NaOH, 7.1 g 1-(3,4-methylenedioxyphenyl)-2-pentanone (see the recipe for METHYL-K for its preparation), and finally 40 mL IPA. The reaction mixture was periodically heated on the steam bath to keep the reaction moving and active. After all the metal had been consumed, the mixture was filtered, and the filter cake washed with MeOH. The solvent was removed from the combined filtrate and washings, and the residue suspended in 800 mL dilute HCl. This was washed with 3x100 mL Et2O, made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum yielding a residue of 6.3 g of an amber oil. This was distilled at 115-125 !C at 0.4 mm/Hg to give 5.61 g of an almost white liquid which was dissolved in 28 mL IPA, neutralized with concentrated HCl, and diluted with 100 mL anhydrous Et2O. The resulting clear solution became cloudy, then set up in a cottage cheese texture, and then all broke up to a beautiful loose solid. This was filtered, Et2O washed and air dried to give 5.99 g 2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane hydrochloride (ETHYL-K) with a mp of 157-158 !C. Anal. (C14H22ClNO2) C,H. DOSAGE: (greater than 40 mg). DURATION: unknown. QUALITATIVE COMMENTS: (with 40 mg) There was a paresthetic twinge in my shoulder area at about an hour Q other than that, absolutely nothing. EXTENSIONS AND COMMENTARY: And that is as high a dose as has apparently ever been tried with ETHYL-K. The compounds with the hexane chain (L-series) rather than the pentane chain of the K-series have been made, but they have been spun into the recipe for METHYL-K. #79 F-2; 2-M; 6-(2-AMINOPROPYL)-5-METHOXY-2-METHYL-2,3-DIHYDROBENZOFURAN SYNTHESIS: To a solution of 43.2 g KOH pellets in 250 boiling EtOH there was added 96 g 4-methoxyphenol followed by the slow addition of 131.2 g allyl bromide, and the mixture was held under refluxing conditions for 16 h. After cooling, the reaction was added to 1.6 L H2O, and made strongly basic with 25% NaOH. This was extracted with 3x100 mL CH2Cl2, the extracts pooled, washed once with dilute NaOH and then once with dilute HCl. Removal of the solvent under vacuum gave 93.8 g of 4-allyloxyanisole as a pale amber oil, which was used in the following reaction without further purification. A round-bottomed flask containing 93 g crude 4-allyloxyanisole was equipped with an immersed thermometer and heated with an external flame until an exothermic reaction set in at 230 !C. The temperature rose to 270 !C and it was maintained there with the flame for five minutes. After cooling to room temperature, the reaction mix was poured into 2 L H2O and made strongly basic with the addition of 25% NaOH. This dark aqueous phase was washed with 2x200 mL CH2Cl2, and then acidified with HCl. This was then extracted with 2x200 mL CH2Cl2, and the pooled extracts washed first with saturated NaHCO3 and then with H2O. Removal of the solvent under vacuum gave 65.6 g of 2-allyl-4-methoxyphenol as a clear, amber oil. To a solution of 1.66 g of this crude phenol in 5 mL hexane with just enough CH2Cl2 added to effect a clear solution, there was added 1.3 g phenyl isocyanate followed with three drops of triethylamine. An exothermic reaction ensued which spontaneously deposited white crystals. These was removed and hexane washed to give 2-allyl-4-methoxyphenyl N-phenyl carbamate, with a mp of 88-89 !C. The acetate ester, from the phenol and acetic anhydride in pyridine, did not crystallize. To a solution of 37.7 g 2-allyl-4-methoxyphenol in 125 mL glacial acetic acid there was added 19 g zinc chloride followed with 63 mL concentrated HCl. The mixture was held at reflux temperature for 40 min, then cooled to room temperature, diluted with 300 mL H2O, and extracted with 2x200 mL CH2Cl2. The pooled extracts were washed repeatedly with 8% NaOH until the washings remained basic. Removal of the solvent under vacuum gave a clear pale yellow oil that was distilled at the water pump. A fraction boiling at 150-165 !C was 5-methoxy-2-methyl-2,3-dihydrobenzofuran which weighed 25 g and which was a highly refractive colorless oil. The infra-red spectrum indicated that some small amount of hydroxy group was present, but the NMR spectrum was in complete accord with the benzofuran structure. A higher cut in this distillation gave 4.5 g of a phenolic product tentatively assigned the structure of 4-methoxy-2-propenylphenol. The target dihydrobenzo-furan has also been synthesized from the open-ring o-allyl phenol in acetic acid solution with the addition of a catalytic amount of concentrated H2SO4. To a half-hour pre-incubated mixture of 69 g POCl3 and 60 g N-methylformanilide there was added 29.0 g 5-methoxy-2-methyl-2,3-dihydrobenzofuran and the mixture was heated on the steam bath for 2 h. The reaction mixture was poured into 1 L H2O, and allowed to stir overnight. The brown gummy solids were removed by filtration, and air dried as completely as possible. These weighed 32 g and were shown by GC on OV-17 to consist of two benzaldehyde isomers in a ratio of 7:2. This was triturated under 18 mL MeOH, and the undissolved solids removed by filtration and washed with 6 mL additional MeOH. The mother liquor and washings were saved. The 17.8 g of dull yellow solids that were obtained were repeatedly extracted with 75 mL portions of boiling hexane (4 extracts were required) and each extract, on cooling, deposited yellow crystals of the major aldehyde. The dried crystals of 6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran were combined (9.5 g) and had a mp of 80-82 !C. The methanol washes saved from above were stripped of solvent, and the sticky, orange solids that remained were enriched in the minor aldehyde isomer (3:2 ratio). Several injections of this crude material into a preparative GC OV-17 column gave sufficient quantities of the RwrongS isomer for NMR characterization. The 2-methyl group was intact (eliminating the possibility of a dihydrobenzopyran isomer) and the ring meta-proton splitting required that the formyl group be in the benzofuran 7-position. This crystalline solid was, therefore, 7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran. A solution of 9 g of 6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran in 35 mL glacial acetic acid was treated with 6 mL of nitroethane followed with 3.1 g anhydrous ammonium acetate. This mixture was heated on the steam bath for 4 h, diluted with half its volume with warm H2O, and seeded with a bit of product that had been obtained separately. The slightly turbid solution slowly crystallized as it cooled, and was finally held at 0 !C for several h. The deep orange product was removed by filtration, washed with 50% acetic acid, and air dried to constant weight. There was thus obtained 7.0 g 5-methoxy-2-methyl-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran with a mp of 89-90 !C from MeOH. A suspension of 5.0 g LAH in 500 mL of well stirred anhydrous Et2O at a gentle reflux, was treated with a warm, saturated solution of 7.0 g 5-methoxy-2-methyl-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran in Et2O added dropwise. The mixture was kept at reflux temperature for 36 h, allowed to stand 2 days, and then the excess hydride destroyed by the cautious addition of 500 mL 6% H2SO4. The phases were separated, and the aqueous phase washed with 2x200 mL CH2Cl2. A total of 125 g potassium sodium tartrate was added to the aqueous phase, and sufficient 25% NaOH added to bring the pH to about 10. This phase was extracted with 3x150 mL CH2Cl2, and the pooled extracts were stripped of solvent under vacuum. The residual oil (4.8 g, amber in color) was dissolved in 300 mL anhydrous Et2O which, upon saturation with anhydrous HCl gas gave a clear solution that suddenly deposited white crystals. The hydrochloride salt of 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran weighed 2.3 g and was not satisfactory as a solid derivative, but it appears that the oxalate salt is both nonhygroscopic and quite stable. It (F-2) had a mp of 216-218 !C and it displayed a textbook NMR. DOSAGE: greater than 15 mg. DURATION: unknown. EXTENSIONS AND COMMENTARY: This material, which is certainly a mixture of two diastereoisomeric pairs of racemates since there are two chiral centers present, showed no effects at levels of up to 15 milligrams orally. Doses of 100 mg/Kg were without effects in mice following i.p. injections, although half again this amount proved to be lethal. In rats trained to discriminate LSD from saline, F-2 proved to be about 40 times less potent than the reference compound DOM, requiring some 5 mg/Kg for positive responses. But the human trials were only up to about 0.2 mg/Kg. This was the prototype compound that was originally put together to justify giving a paper at a marijuana conference in Sweden, in 1968. Although I had never done much with marijuana or with its principal ingredients, I thought maybe I could bend the topic a bit to embrace some potentially active phenethylamines. There is a story of an international conference held in Geneva a few years earlier to discuss the worrisome decrease in the elephant population. A German zoologist invested a full eight-hour day in a summary of his 21 volume treatise on the anatomy and the physiology of the elephant. A French sociologist presented a lively slide show on the mating rituals and rutting behavior of the elephant. And a rabbi from Tel Aviv entitled his talk: RElephants and the Jewish Problem.S My Swedish talk should have been named RMarijuana and the Psychedelic Amphetamines.S The memorable story of meeting the chief of the Swedish equivalent of the Bureau of Narcotics, and ending up playing Mozart sonatas in the attic of his home, has been spun out elsewhere in the book. The original concept was a grand plan to imitate two of the three rings of tetrahydrocannabinol. There is an aromatic ring (with an alkyl group and two oxygens on it) and it is fused to a pyran ring with a couple of methyl groups on it. So, if one were to tie the methyl group at the 4-position of DOM around with a short carbon chain into the oxygen atom at the five position, one could squint and say that the resulting amphetamine was kinda something like an analogue of THC. Thus, the resulting six-membered ring (a pyran) or five-membered ring (a furan) could be peppered with methyl groups at different locations (and up to two per location). If the ring was a five-membered structure, then the parent system would be a benzofuran, and the location of methyl groups on the ring would be indicated by the appropriate numbers following the letter RFS which would stand for RfuranS. And if it were to be a six-membered ring, the resulting benzopyran would be indicated with a RPS for pyran, and again the methyl group or groups would be indicated by the substitution position. This code would cover all polymethylated homologues with codes that would look like F-22 and P-2234. If any of them showed up with fascinating activities, I would extend methyls to ethyls, and work out some whole new naming code at some future time. An early system, naming this compound 2-M for a methyl group on the 2-position of the furan ring, was abandoned when it became apparent that the pyran world would screw everything up. The isolation of characterizable quantities of 7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran from the benzaldehyde recipe above gave a fleeting fantasy of a whole new direction that this little project might go. If this unexpected benzaldehyde were to be converted to the corresponding amphetamine, one would have 7-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran. Suddenly here would be a 2,3,5-trisubstituted thing with a ring at the 2,3-position, similar to the still unmade MMDA-4. The temptation to be diverted in this way lasted, fortunately, only a few minutes, and the project was shelved. Someday, when there are buckets of spare time or hosts of eager graduate students, some fascinating chemistry might lie this way, and maybe some fascinating pharmacology, even. The plain furan analogue, without any methyl groups on it, has been made. Five-methoxybenzofuran formed the 6-formyl derivative (the aldehyde) with a mp of 79-80 !C and from it the nitrostyrene (orange needles, mp 89-91 !C) and the final amphetamine (white solids, as the methane sulfonate, mp 141-144 !C) were prepared in a manner similar to the preparation of F-2 above. In the rat studies, it was three times more potent than F-2, but still some 15 times less potent than DOM. And in initial human trials (of up to 30 milligrams) there were again no effects noted. Naming of this material is easy chemically (6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran) but tricky as to code. If the numbers that follow the RFS give the location of the methyl groups, then this material, without any such groups, can have no numbers following, and should properly be simply RF.S OK, it is RF.S The preparation or the attempted preparations of other homologues such as F-23 and F-233 are outlined under the recipe for F-22. #80 F-22; 6-(2-AMINOPROPYL)-2,2-DIMETHYL-5-METHOXY-2,3-DIHYDROBENZOFURAN SYNTHESIS: To a solution of 43.2 g flaked KOH in 250 mL hot EtOH there was added 96 g 4-methoxyphenol followed by 90 g 2-methylallyl chloride over the course of 2 h. The mixture was held at reflux for 24 h, then added to 1.6 L H2O. There was sufficient 25% NaOH added to make the phase strongly basic, and this was then extracted with 3x200 mL CH2Cl2. The pooled extracts were washed with H2O, and the solvent removed under vacuum. The residue, 125 g of a pale amber oil, was crude 4-(2-methylallyloxy)anisole and was used without further purification in the following reaction. In a round-bottomed flask containing an internal thermometer, there was placed 125 g of unpurified 4-(2-methylallyloxy)anisole, and this was heated with an open flame. At an internal temperature of 190 !C an exothermic reaction set in, raising the temperature to 250 !C, where it was held for an additional 2 min. After the reaction mixture had cooled to room temperature, it was poured into 500 mL H2O, made strongly basic with 25% NaOH, and extracted repeatedly with 100 mL portions of CH2Cl2 until the extracts were essentially colorless. These extracts were pooled and the solvent removed to provide 80.0 g of a deeply colored oil that proved to be largely the appropriately substituted dihydrobenzofuran. The aqueous residue from above was acidified with concentrated HCl, and again extracted with CH2Cl2. Removal of the solvent gave 17.7 g of 4-methoxy-2-(2-methylallyl)phenol as an amber oil which eventually set down as white crystals with a mp of 52.5-54 !C. A solution of 17 g of 4-methoxy-2-(2-methylallyl)phenol in 56 g acetic acid was treated with 8.4 g zinc chloride followed with 28 mL concentrated HCl. This mixture was heated at reflux temperature with a mantle for 1 h. After cooling, this was poured into H2O and extracted with 2x150 mL CH2Cl2. The pooled extracts were washed with several portions of 8% NaOH, until the extracts were colorless. The organic fraction was then washed with H2O, and the solvent removed to yield 5.8 g of 2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran as a pale amber oil with a pungent smell. This was purified by distillation, giving a fraction of an off-white oil with a bp of 136-138 !C at 33 mm/Hg. To a mixture of 8.0 g N-methylformanilide and 9.2 g POCl3 which had been allowed to stand for 0.5 h, there was added 4.0 g 2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran, and the mixture held at the steam bath temperature for 2.5 h. This was then poured into 200 mL H2O which produced a black oily phase that gave no hint of crystallization. This mixture was extracted with 3x150 mL CH2Cl2 and the solvent was removed from the pooled extracts under vacuum. The residual oil (which was shown by GC to contain approximately equal quantities of two isomeric benzaldehydes A and B) was extracted with three 75 mL portions of boiling hexane, each of which on cooling deposited a reddish oil that partially crystallized. A fourth hexane extract gave nothing more. The solvent was decanted from these three extracts, and the semi-solid residues were ground under 3.0 mL MeOH giving 1.4 g of pale yellow crystals of 2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydrobenzo-furan, isomer RBS. After recrystallization from MeOH, the color was almost white, and the mp was 79.5-80.5 !C. The combined mother liquors were enriched in isomer RAS which proved, following preparative GC separation and NMR analysis, to be the 7-formyl isomer. The 80 g of impure dihydrobenzofuran isolated from the Claisen rearrangement above was distilled and a fraction (43.8 g) that boiled from 138-153 !C at 30 mm/Hg was processed as described here to the aldehyde mixture. Following similar hexane extractions, a yield of 4.0 g of a 95% pure isomer RBS was finally obtained. The remaining components of this fraction were not determined, but it is possible that there were some that contained the six-membered benzopyran ring system. To a solution of 5.2 g of 2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydro-benzofuran in 20 mL glacial acetic acid there was added 3 mL nitroethane followed by 1.6 g anhydrous ammonium acetate. This mixture was heated for 4 h on the steam bath, and then a small amount of H2O was added to the hot solution. This instigated the formation of a copious deposition of brick-red crystals which were, after cooling, removed by filtration, and recrystallized from 50 mL boiling MeOH. After air drying there was thus obtained 2.7 g of day-glo yum-yum orange crystals of 2,2-dimethyl-5-methoxy-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran. An additional 0.6 g of product was obtained by working the mother liquors. A suspension of 2.5 g LAH in 300 mL refluxing anhydrous Et2O was treated with a solution of 3.1 g 2,2-dimethyl-5-methoxy-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran in Et2O. The mixture was held at reflux temperature for 18 h. After cooling, the excess hydride was destroyed by the cautious addition of 400 mL H2O which contained 15 g H2SO4. The aqueous phase was separated, washed once with Et2O, and then once with CH2Cl2. There was then added 60 g potassium sodium tartrate, and the pH was brought to above 10 by the addition of 25% NaOH. This was extracted with 3x250 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. There remained 2.8 g of an amber oil with an ammoniacal smell. This was dissolved in 200 mL anhydrous Et2O, and saturated with anhydrous HCl gas. There was the immediate formation of an oil, from which the supernatent Et2O was decanted. The residual oil was resuspended in a second 200 mL anhydrous Et2O, again decanted, and finally a third 200 mL Et2O effected the dissolving of the remaining oil to give a clear solution. All three solutions became gelatinous over the following few h, and each deposited a crop of white crystals over the following few days. From the first there was obtained 1.4 g of product with a mp of 153-154 !C; from the second, 0.2 g with a mp of 153-154 !C; and from the third, 1.2 g with a mp of 155-156 !C. These crops were combined, and recrystallized from 10 mL of boiling CH3CN to give 1.7 g 6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran hydrochloride (F-22) as a white crystalline solid which had a mp of 154-155 !C. This material, even when dry, showed a tendency to discolor with time. DOSAGE: greater than 15 mg. DURATION: unknown. EXTENSIONS AND COMMENTARY: And here is yet another dihydrobenzofuran which is not of a very high potency if, indeed, it is active at all. This particular dihydrobenzofuran analogue, F-22, had sort of tickled my fancy as being an especially good candidate for activity. It had a certain swing to it. F-22, like LSD-25. And here it was finished, just five days before I had to deliver a paper concerning the syntheses (and activities!) of all these dihydrobenzofurans to the marijuana congress. Could this possibly be another LSD? I was sufficiently convinced that the possibility was real, that I actually started the screening process at a most unusually low level of 10 micrograms. Two days later, I upped this to a dose of 25 micrograms (no activity again) and three days after that, at 1 AM on the polar flight to Copenhagen, I swallowed the RmonstrousS dose of 50 micrograms. Shoot the works. If I were to blossom all over the tourist section of the SAS plane, well, it would be quite a paper to give. If not, I could always say something like, RThe active level has not yet been found.S No activity. Another Walter Mitty fantasy down the tubes. And, as it turned out, the entire project pretty much ran out of steam. A number of clever analogs had been started, and would have been pursued if there had been any activity promised of any kind with any of these dihydrobenzofurans. The RotherS benzaldehyde described above, could have been run in a manner parallel to that proposed for the counterpart with F-2, to make the eventual amphetamine, 7-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran. Great strides had been made towards F-233 (I have discussed the naming system under F-2, with the F standing for the furan of benzofuran and the 2 and 3 and 3 being the positions of the methyl groups on it). The reaction of 4-methoxyphenol with 1-chloro-3-methyl-2-butene gave the ether which underwent the thermal Claisen rearrangement to 2-(1,1-dimethylallyl)-4-methoxyphenol with a bp of 148-157 !C at 30 mm/Hg. This was cyclized to the intermediate cycle 2,3,3-trimethyl-2,3-dihydrobenzofuran which, after distillation, was shown to be only 80% pure by GC analysis. This was, nonetheless, (and with the hope that is in the very fiber of a young innocent chemist), pushed on to the benzaldehyde stage (and there were a not-too-surprising four benzaldehydes to be found in the oil that was produced, which refused to crystallize). And then (when sheer desperation replaced hope) these were condensed with nitroethane to form an even worse mixture. Maybe something might crystallize from it? Nothing ever did. Junk. Everything was simply put on the shelf where it still rests today, and F-233, 6-(2-aminopropyl)-5-methoxy-2,3,3-trimethyl-2,3-dihydrobenzofuran, remains the stuff of speculation. And a start towards F-23, 6-(2-aminopropyl)-2,3-dimethyl-5-methoxy-2,3-dihydrobenzofuran, got just as far as the starting ether, when it occurred to me that the final product would have an unprecedented three chiral centers, and so a total of four racemic pairs of diastereoisomers. And then I discovered that the starting allyl halide, crotyl chloride, was only 80% pure, with the remaining 20% being 3-chloro-1-butene. This would have eventually produced a 2-ethyl-analogue, 6-(2-aminopropyl)-2-ethyl-5-methoxy-2,3-dihydrobenzofuran, with its two chiral centers and two more pairs of stereoisomers (not to speak of the need to devise an entirely new coding system). Unless something were to fall into my lap as a crystalline intermediate, the final mess could have had at least six discreet compounds in it, not even considering optical isomers. And I havenUt even begun to think of making the six-membered dihydrobenzopyrans which were the THC analogues that presented the rationale that started the whole project in the first place. A recent issue of the Journal of Medicinal Chemistry has just presented an article describing the reaction of 6-methoxytetrahydrobenzopyran with dichloromethyl methyl ether, and approximately equal amounts of all three of the possible isomers were obtained. That would have been the first step towards making the prototypic compound 7-(2-aminopropyl) 6-methoxy-1,2,3,4-tetrahydrobenzopyran. Just as the benzofurans were all named as F-compounds, this, as a benzopyran, would have been a P compound, but P also is used for proscaline, and there would have been some repair-work needed for these codes. Time to abandon ship. The fact that I had just synthesized and discovered the strange activity of ARIADNE at about this time, made the ship abandonment quite a bit easier to accept. #81 FLEA; N-HYDROXY-N-METHYL-3,4-METHYLENEDIOXYAMPHETAMINE SYNTHESIS: (from 3,4-methylenedioxyphenylacetone) A solution of 2.1 g N-methylhydroxylamine hydrochloride and 4.4 g 3,4-methylenedioxyphenylacetone in 5.5 mL MeOH was added to a suspension of 4.5 g NaHCO3 in 30 mL boiling MeOH. There was added about 5 mL H2O (which gave a clear solution) followed by another 50 mL H2O which produced a pale yellow color. To this solution of the unisolated nitrone there was added 1.7 g sodium cyanoborohydride, which generated a goodly amount of foaming. There was HCl added as needed to maintain the pH at about neutrality. The reaction appeared to have stopped after a day or two, so all was poured into 500 mL H2O, acidified with HCl, and washed with 2x75 mL CH2Cl2. The addition of base brought the pH >9, and this was then extracted with 3x75 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a residue of 1.65 g of crude N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine. Efforts to obtain solid seed samples of the salts with hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, and with a number of organic acids, all failed. The salt formation from this free-base will be discussed below. (from MDOH) A solution of 0.75 g crystalline free-base MDOH in a few mL MeOH was treated with a solution of 0.4 g sodium cyanoborohydride in 10 mL MeOH, and there was then added 2 mL of 35% formaldehyde. The stirred reaction mixture was kept at a neutral pH with the occasional addition of HCl. After several days (when additional acid was no longer required) the excess solvent was removed under vacuum, and the residue poured into dilute H2SO4. This was washed with 2x75 mL CH2Cl2 and then, following the addition of base, this was extracted with 3x75 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a viscous oil residue of 0.53 g. The free-base product from these preparations was distilled at 110-120 !C at 0.2 mm/Hg to give the N-hydroxy-N-methyl product as a white oil. An alternate methylation procedure used a solution of MDOH in a 4:1 MeOH/acetic acid solution containing formaldehyde which was reduced with sodium borohydride at dry ice temperatures. Its work-up is identical to that involving sodium cyanoborohydride. The distilled product was dissolved in an equal volume of MeOH, and treated with a half-equivalent of oxalic acid dihydrate, dissolved in 10 volumes of MeOH. This combination gave the slow deposition of crystals of the full oxalate salt (one acid, two bases) as a white crystalline product. The mp of the crude salt was in the 130-150 !C range, and after recrystallization from CH3CN, N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine oxalate (FLEA) had a mp of 146-147 !C. DOSAGE: 100 - 160 mg. DURATION: 4 - 8 h. QUALITATIVE COMMENTS: (with 90 mg) The material tastes terrible, like grapefruit juice that has stayed in the can too long. There was no nausea, no feeling of difficulty in swallowing at any time during the day. I felt a dry mouth and was thirsty Q sipped water throughout the day. At the beginning of the experiment, there was a glimmer of the MDMA warmth, but later I felt separated and a bit isolated. I was just floating around, seeing the beauty of colors and objects in the house and outdoors and listening first to this conversation, then to that one. All senses seemed enhanced. I found the material pleasant. I was happy with the amount I took but would not be afraid to take more or to take a supplement. I found it similar to, but not the same as, MDMA. (with 110 mg) We found this very similar to MDMA, but perhaps slightly slower. I plateauUd at 2:30 hours and had a very gradual descent. My friend had a marvelous and private 'cone of silence' that was to him unique to MDMA or to 2C-T-8. Teeth problems were minor, and the descent from the top of the experience showed less interactive, and more contemplative action, than with MDMA. Very similar to MDMA, but with its own character. (with 110 mg) The onset was at about a half-hour. The come-on was more gradual and much easier than with MDMA, and it seemed to be more head than body oriented. I had about two hours of very complex and personal self-evaluation, and I am not at peace in putting all of it down here in writing. Overall I like it, and I would be interested to see if there's a difference in conjunction with MDMA. Thanks very much. (with 110 mg + 35 mg) I saw my onset at 20 minutes, and it was subtle, and very pleasant, and had a mild amphetamine-like elevation for me (body lightness, cognitive functions seemed clear and clean, heightened visual awareness and with some enhancement of color). It seemed as if I were on the fringe of LSD-like visual changes, but that never materialized. The affect was very good, communicative, friendly, accepting, but without the profound emotional bonding of MDMA. The following day felt very much like a post-LSD day; we felt great. The body was light, energy good, emotions high, several insights throughout the day, interactions clear and open Q a magnificent gift of a day. I started a menstrual period the day of the experience and it lasted 6 to 7 days; all of this was a couple of weeks early. I have a very favorable impression of FLEA although the body penalty seems high. EXTENSIONS AND COMMENTARY: Most people who were involved with the evaluation of FLEA quite logically compared it with MDMA, as it was presented as being a very close analogue which might share some of the latter's properties. And to a large measure, the comparison was favorable. The dosages are almost identical, the chronological course of action is almost identical, and there are distinct similarities in the effects that are produced. If there is a consensus of similarities and differences it would be that it is not quite as enabling in allowing a closeness to be established with others. And perhaps there is more of a move towards introspection. And perhaps a slightly increased degree of discoordination in the thought processes. But also, part of this same consensus was that, were MDMA unknown, this material would have played its role completely. And from the scientific point of view, it lends more weight to a hypothesis that just might be a tremendous research tool in pharmacology. I first observed the intimate connection between an amine and a hydroxylamine with the discovery that N-hydroxy-MDA (MDOH) was equipotent and of virtually identical activity to the non-hydroxylated counterpart (MDA). And I have speculated in the recipe for MDOH about the possible biological interconversions of these kinds of compounds. And here, the simple addition of a hydroxyl group to the amine nitrogen atom of MDMA produces a new drug that is in most of its properties identical to MDMA. The concept has been extended to 2C-T-2, 2C-T-7, and 2C-T-17, where each of these three active compounds was structurally modified in exactly this way, by the addition of a hydroxyl group to the amine nitrogen atom. The results, HOT-2, HOT-7 and HOT-17 were themselves all active, and compared very closely with their non-hydroxylated prototypes. Just how general might this concept be, that an N-hydroxyl analog of an active amine shall be of similar action and duration as the parent drug? What if it really were a generality! What havoc it would wreak in the pharmaceutical industry! If I could patent the concept, then I would be able to make parallel best sellers to all of the primary and secondary amines out there in the industry. Perhaps 90% of all the commercially available drugs that are concerned with the human mental state are amines. And a goodly number of these are primary or secondary amines. And each and every one of these could be converted to its N-hydroxyl analogue, effectively by-passing the patent protection that the originating corporation so carefully crafted. An example, just for fun. A run-away best seller right now is an antidepressant called fluoxetine, with the trade name Prozac. I will make a small wager that if I were to synthesize and taste N-hydroxy-N-methyl-3-phenyl-3-((a,a,a-trifluoro-p-tolyl)oxy)propylamine, I would find it to be an active antidepressant. Remember, Mr. Eli Lilly and Company; you read about it first, right here! Of course, I was asked, why call it FLEA? The origin was in a classic bit of poetry. A commonly used code name for MDMA was ADAM, and I had tried making several modest modifications of the MDMA structure in the search for another compound that would maintain its particular music without the annoying tooth-grinding and occasional nystagmus, or eye-wiggle, that some users have mentioned. One of these was the 6-methyl homologue which was, with some perverse logic, called MADAM. And, following this pattern, the 6-fluoroanalogue was to be FLADAM. So, with the N-hydroxy analogue, what about HADAM? Which brought to mind the classic description of Adam's earliest complaint, an infestation of fleas. The poem was short and direct. RAdam had Uem. So, in place of HAD UEM, the term FLEA jumped into being. #82 G-3; 2,5-DIMETHOXY-3,4-(TRIMETHYLENE)AMPHETAMINE; 5-(2-AMINOPROPYL)-4,7-DIMETHOXYINDANE SYNTHESIS: A solution of 3.7 g of 2,5-dimethoxy-3,4-(trimethylene)benzaldehyde (see preparation under 2C-G-3) in 15 mL nitroethane was treated with 0.7 g anhydrous ammonium acetate and heated on the steam bath for 2.5 h. The excess solvent was removed under vacuum leaving some 5 mL of a deep orange-red oil which on cooling, spontaneously crystallized. This was finely ground under 10 mL MeOH, filtered, washed sparingly with MeOH, and air dried to give 3.6 g of orange crystals with a strong smell of old acetamide. The mp was 92-93 !C. All was recrystallized from 30 mL boiling MeOH to give, after filtering and drying, 2.9 g of 1-(2,5-dimethoxy-3,4-(trimethylene)phenyl)-2-nitropropene as yellow crystals with a mp of 93-94 !C. Anal. (C14H17NO4) C,H,N. Fifty milliliters of 1 M LAH in THF was placed in an inert atmosphere, well stirred, and cooled to 0 !C with an external ice-bath. There was added, dropwise, 1.35 mL of 100% H2SO4 at a rate slow enough to minimize charring. There was then added, dropwise, 2.8 g 1-(2,5-dimethoxy-3,4-(trimethylene)phenyl)-2-nitropropene in 15 mL THF. At the end of the addition, the stirring was continued for an additional 0.5 h, and then the reaction mixture was held at reflux on the steam bath for another 0.5 h. After cooling again to ice-bath temperature, the excess hydride was destroyed with the addition of 11 mL IPA, followed by 5.5 mL 5% NaOH which converted the inorganic mass through a cottage cheese stage into a loose, filterable texture. The solids were removed by filtration, washed with additional THF, and the combined filtrates and washes stripped of solvent under vacuum. There was obtained 2.51 g of a white oil that was distilled at 115-135 !C at 0.2 mm/Hg to give 1.83 g of a clear colorless oil. This was dissolved in 8 mL IPA, neutralized with 28 drops of concentrated HCl, and diluted with 140 mL anhydrous Et2O. In about 0.5 h there started a slow snowfall of fine fluffy white crystals which was allowed to continue until no additional crystals appeared. After filtering, Et2O washing and air drying, there was obtained 1.81 g of 2,5-dimethoxy-3,4-(trimethylene)amphetamine hydrochloride (G-3) with a mp of 157-159 !C. Anal. (C14H22ClNO2) C,H. DOSAGE: 12 - 18 mg. DURATION: 8 - 12 h. QUALITATIVE COMMENTS: (with 12 mg) There was a warmth, a mellowness, as things developed. No body disturbance at all, but then there were no visuals either which, for me on this particular occasion, was disappointing. The day was consumed in reading, and I identified completely with the character of my fictional hero. It was a different form of fantasy. I think I prefer music as a structural basis for fantasy. (with 18 mg) I am at a plus three, but I am not at all sure of why it is a plus three. With my eyes closed, there are puffy clouds, but no drama at all. Music was not exciting. There could well have been easy eroticism, but there was no push in that direction. No great amount of appetite. Not much of anything, and still a plus three. Simply lying still and surveying the body rather than the visual scene gave some suggestions of neurological sensitivity, but with getting up and moving about and doing things, all was fine. The next morning I was perhaps moving a bit more slowly than usual. I am not sure that there would be reward in going higher. EXTENSIONS AND COMMENTARY: In a comparison between the 2-carbon compound (2C-G-3) and the 3-carbon compound (G-3) the vote goes towards the phenethylamine (the 2-carbon compound). With the first member of this series (2C-G versus GANESHA) this was a stand-off, both as to quantitative effects (potency) and qualitative effects (nature of activity). Here, with the somewhat bulkier group located at the definitive 3,4-positions, the nod is to the shorter chain, for the first time ever. The potency differences are small, and maybe the amphetamine is still a bit more potent. But there are hints of discomfort with this latter compound that seem to be absent with the phenethylamine. The more highly substituted compounds (q.v.) more clearly define these differences. #83 G-4; 2,5-DIMETHOXY-3,4-(TETRAMETHYLENE)AMPHETAMINE; 6-(2-AMINOPROPYL)-5,8-DIMETHOXYTETRALIN SYNTHESIS: A solution of 1,4-dimethoxy-5,6,7,8-tetrahydro-'-naphthaldehyde (see preparation under 2C-G-4) in 20 mL nitroethane was treated with 0.13 g anhydrous ammonium acetate and heated on the steam bath overnight. The volatiles were removed under vacuum and the residue, on cooling, spontaneously crystallized. This crude rust-colored product (1.98 g) was recrystallized from 15 mL boiling MeOH yielding, after filtering and air drying to constant weight, 1.33 g of 1-(2,5-dimethoxy-3,4-(tetramethylene)phenyl)-2-nitropropene as dull gold-colored crystals. The mp was 94-94.5 !C. Anal. (C15H19NO4) C,H. DOSAGE: unknown. DURATION: unknown. EXTENSIONS AND COMMENTARY: The discussion that appeared in the commentary section under 2C-G-4 applies here as well. The major struggles were in the preparation of the aldehyde itself. And although the final product has not yet been made, this last synthetic step should be, as Bobby Fischer once said in his analysis of a master's chess game following a blunder by his opponent, simply a matter of technique. As with the phenethylamine counterpart, G-4 has a structure that lies intermediate between G-3 and G-5, both potent compounds. It is axiomatic that it too will be a potent thing, and all that now needs be done is to complete its synthesis and taste it. #84 G-5; 3,6-DIMETHOXY-4-(2-AMINOPROPYL)BENZONORBORNANE SYNTHESIS: A solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane (see under 2C-G-5 for its preparation) in 20 g nitroethane was treated with 0.88 g anhydrous ammonium acetate and held at steam bath temperature overnight. The excess solvent and reagent was removed under vacuum to yield a residual yellow oil. This was allowed to stand at ambient temperature for a period of time (about 3 years) by which time there was a spontaneous crystallization. The dull yellow crystals were removed by filtration and, after air drying, weighed 4.28 g. A small sample was recrystallized repeatedly from MeOH to provide a pale yellow analytical sample of 3,6-dimethoxy-4-(2-nitropropenyl)benzonorbornane with a mp of 90-91 !C. Anal. (C16H19NO4) C,H. A solution of LAH (50 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 1.32 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 4.1 g 3,6-dimethoxy-4-(2-nitropropenyl)benzonorbornane in 20 mL anhydrous THF over the course of 10 min. The reaction mixture was stirred and brought to room temperature over the course of 1 h. This was then brought to a gentle reflux on the steam bath for 0.5 h, and then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of 10 mL IPA followed by 5 mL 5% NaOH and sufficient H2O to give a white granular character to the oxides. The reaction mixture was filtered, and the filter cake washed with THF. The filtrate was stripped of solvent under vacuum providing a pale amber oil that was distilled at 125-140 !C at 0.2 mm/Hg to give 2.5 g of an almost white oil. This was dissolved in 10 mL IPA, neutralized with 25 drops of concentrated HCl, and then diluted with 140 mL anhydrous Et2O. There appeared, after about two minutes, white crystals of 3,6-dimethoxy-4-(2-aminopropyl)benzonorbornane hydrochloride (G-5) which, after filtration and air drying, weighed 2.47 g. DOSAGE: 14 - 20 mg. DURATION: 16 - 30 h. QUALITATIVE COMMENTS: (with 15 mg) As part of the audience at the San Francisco conference, Angels, Aliens and Archtypes, I could simply listen and observe without having to participate. Each speaker stood in a cone of light that was beautifully bright and colorful, casting everything else on the stage into obscurity. Maybe angels really are illuminated from above, and the aliens lurk out of sight until it is their turn. Where does one look for the archetypes? A half of a cream cheese sandwich was all I could eat, and even at dinner that evening I was not hungry. Sleep that evening was difficult. (with 20 mg) Very slow to come on, but then it was up there all of a sudden. There is an unexpected absence of visual activity despite being at a full +++. The mental activity is excellent, with easy writing and a positive flow of ideas. But an absence of the bells and whistles that are expected with a psychedelic in full bloom. There is a real drop by the 16th hour and the next day was free of effect except for occasional cat-naps. (with 20 mg) The transition period, which usually lasts for most compounds for the first hour or two, with this seems to be much longer. This presages a long-acting material, as usually the slow-in slow-out rule applies. But there are exceptions. There is an indifference towards the erotic, but no separation at all from personal interactions and emotions. I believe in integration, not separation of all parts of ourselves, distrusting any drug states (particularly those that have the reputation of being strongly Tcosmic)U which divorce the consciousness from the body. And with this material there is no separation from feelings, only from my particular color language. EXTENSIONS AND COMMENTARY: This is as potent as any of the three-carbon Ganesha compounds, but it somehow lacks a little something that would have made it a completely favorite winner. Perhaps it is the generally commented upon absence of visual and related sensory entertainment. There seems to be no bodily threat to discourage further exploration, but there simply was not the drive to explore it much. The comments concerning the enlargement of the ring system (mentioned under 2C-G-5) are equally valid here. The RshrubberyS that is the hallmark of the Ganesha family is, with G-5, about as bulky as has ever been put onto a centrally active molecule. The norbornane group has a one carbon bridge and a two carbon bridge sticking out of it at odd angles. The replacement of the one-carbon bridge with a second two-carbon bridge would make the compound G-6. It would be makeable, but is there really a driving reason to do so? There is a simplification intrinsic in this, in that G-5 actually has two centers of asymmetry (the a-carbon atom on the amphetamine chain, and the norbornyl area itself) and so it is really a mixture of two racemic diastereoisomers. G-6 would still be a racemate, but it would be only a single compound, as are all the other substituted amphetamine derivatives. Someday I may try making G-6, but it's not a high priority right now. #85 GANESHA; G; 2,5-DIMETHOXY-3,4-DIMETHYLAMPHETAMINE SYNTHESIS: A solution of 15.4 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde (see under 2C-G for the preparation) in 50 mL nitroethane was treated with 3 g anhydrous ammonium acetate and heated on the steam bath for 12 h. The excess nitroethane was removed under vacuum, and the residual oil was diluted with a equal volume of MeOH. There was the slow generation of deep red cottage-cheese-like crystals which were removed by filtration and air-dried to constant weight (9.3 g) with a mp 71-74 !C. Recrystal-lization from MeOH (10 ml/g) gave an analytical sample of 1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-nitropropene with a mp of 82 !C sharp. Anal. (C13H17NO4) C,H,N. The NMR spectra (in CDCl3) and CI mass spectrograph (MH+ = 252) were proper. To a suspension of 3.3 g LAH in 200 mL refluxing THF, well stirred and maintained under an inert atmosphere, there was added 4.2 g 1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-nitropropene in 25 mL THF. The mixture was held at reflux for 48 h. After cooling, 3.3 mL H2O was added cautiously to decompose the excess hydride, followed by 3.3 mL 15% NaOH and finally another 10 mL H2O. The inorganic solids were removed by filtration, and washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the residue (4.7 g of a deep amber oil) dissolved in dilute HCl. This was washed with CH2Cl2 (3x75 mL), then made basic with 5% NaOH and extracted with CH2Cl2. Removal of the solvent under vacuum yielded an amber oil that was distilled (105-115 !C at 0.4 mm/Hg) to give 1.2 g of a white oil. This was dissolved in 8 mL IPA, neutralized with 15 drops of concentrated HCl, and diluted with 250 mL anhydrous Et2O. After a period of time, there was a spontaneous appearance of white crystals which were removed by filtration, Et2O washed, and air dried. Thus was obtained 1.0 g of 2,5-dimethoxy-3,4-dimethylamphetamine hydrochloride (GANESHA) with a mp of 168-169 !C. This was not improved by recrystallization from either EtOAc or nitroethane. Anal. (C13H22ClNO2) N. DOSAGE: 20 - 32 mg. DURATION: 18 - 24 h. QUALITATIVE COMMENTS: (with 24 mg) There was a slow buildup to a ++ or more over the course of about three hours. Extremely tranquil, and no hint of any body toxicity whatsoever. More than tranquil, I was completely at peace, in a beautiful, benign, and placid place. There was something residual that extended into the sleep period, and was possibly still there in the morning. Probably I was simply tired from an inadequate sleep. (with 32 mg) A rapid and full development. Lying down with music, the eyes-closed visuals were quite something. There was sudden awareness of a potential toe cramp which I possibly exaggerated, but it kept spinning itself into my awareness, and somehow locked in with my visual imagery. It was not easy to keep the visual/somatic/ cognitive worlds in their proper places. The almost-cramp went away and I forgot about it. There was a back spasm somewhere in this drama, and it really didnUt matter either. This dosage may be a bit much for good housekeeping, though! Towards the end of the experiment, I looked at a collection of photos from a recent trip to Europe, and the visual enhancement was wonderful. A rolling +++. EXTENSIONS AND COMMENTARY: This compound was the seventh of the ten possible Classic Ladies. I have mentioned the concept already under the discussions on ARIADNE. This is the teutonic replacement of each of the distinguishable hydrogen atoms of DOM with a methyl group. The findings with GANESHA were a total surprise. The extension of a hydrogen in the 3-position of DOM with a methyl group should have a minor influence on its steric association with whatever receptor site might be involved. A much greater impact might come not from the size of the group but from its location. This, coupled with a full order of magnitude of decrease in potency, seemed to call for an involvement of that particular position as being one that is affected by metabolism. And since the activity is decreased, the obvious role is in the blocking of the metabolic promotion of DOM-like things to active intermediates. The remarkable point being emphasized here is that the placement of a dull methyl group at a dull position of the DOM molecule actually inactivated (for all intents and purposes) the activity of DOM. It is not the presence of the methyl that has decimated the potency, but the removal of the hydrogen atom. How can such a hypothesis be explored? A historic premise of the medicinal chemist is that if a structure gives an unusual response in a receptor, vary it slightly and see how the response varies. This is exactly the principle that led to the ten Classic Ladies, and with this particular Lady (who actually turned out to be a gentleman), the same concept should hold. There are two involved methyl groups in GANESHA, one at the 3-position and one at the 4-position. Why not homologate each to an ethyl group, and as a wrap up make both of them into ethyl groups. Look at the differences along two lines of variation; the effects of the homologation of the 3- and 4-positions, coupled with the effects of the homologation intrinsic in the comparison of the two-carbon chain of the phenethylamine with the three-carbon chain of the amphetamine. There are thus six compounds involved in such a study. And they have been named (as have all the other GANESHA analogues) in accordance with the collective carbon inventory in and about these two ring positions. The first two compounds are related to DOET and to 2C-E. Maintain the methyl group at the 3-position but homologate the 4-position to an ethyl. The ring pattern would become 2,5-dimethoxy-4-ethyl-3-methyl, and the phenethylamine and amphetamine would be called 2C-G-12 and G-12 respectively (a one carbon thing, the methyl, at position-3 and a two carbon thing, an ethyl, at position-4). Reversal of these groups, the 3-ethyl homologues of 2C-D and DOM would thus become 2C-G-21 and G-21. And, finally, the diethyl homologues would be 2C-G-22 and G-22. In each of these cases, the paired numbers give the lengths of the chains at the two positions, the 3- and the 4-positions that are part of the GANESHA concept. And this code is easily expandable to longer things such as 2C-G-31 and 2C-G-41, which would be the 3-propyl-4-methyl, and the 3-butyl-4-methyl homologues, resp. Unfortunately, these six initially proposed compounds have so far resisted all logical approaches to synthesis, and are at present still unknown. What has been successfully achieved, the building up of a big bulky hydrocarbon glob at these positions, has rather unexpectedly led to a remarkable enhancement of potency. As with all true exploration into areas of the unknown, the deeper you get, the less you understand. #86 G-N; 1,4-DIMETHOXYNAPHTHYL-2-ISOPROPYLAMINE SYNTHESIS: To a solution of 3.9 g 1,4-dimethoxy-2-naphthaldehyde (see under 2C-G-N for the preparation) in 13.5 mL nitroethane there was added 0.7 g anhydrous ammonium acetate, and the mixture heated on the steam bath for 5 h. The deep orange reaction mixture was stripped of excess solvent under vacuum. The residue was a red oil that, upon dilution with two volumes MeOH, immediately set to orange crystals. This crude product (mp 115-118 !C) was recrystallized from 70 mL EtOH to yield, after filtering and air drying, 3.3 g of 1-(1,4-dimethoxy-2-naphthyl)-2-nitropropene as gold-orange crystals, with a mp of 121-123 !C. Recrystallization from MeOH gave a gold-colored product with a mp of 119-120 !C. Anal. (C15H15NO4) C,H,N. A solution of LAH (50 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 1.32 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 3.12 g 1-(1,4-dimethoxy-2-naphthyl)-2-nitropropene in 40 mL anhydrous THF. After stirring for 1 h, the temperature was brought up to a gentle reflux on the steam bath for 0.5 h, and then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of 16 mL IPA followed by 6 mL 5% NaOH to give a white, filterable, granular character to the oxides, and to assure that the reaction mixture was basic. The reaction mixture was filtered, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum providing 3.17 g of a deep amber oil. Without any further purification, this was distilled at 140-160 !C at 0.3 mm/Hg to give 1.25 g of a pale yellow oil. This was dissolved in 8 mL IPA, neutralized with 20 drops of concentrated HCl, and diluted with 60 mL anhydrous Et2O which was the point at which the solution became slightly turbid. After a few min, fine white crystals began to form, and these were eventually removed, washed with Et2O, and air dried to provide 1.28 g 1,4-dimethoxynaphthyl-2-isopropylamine hydrochloride (G-N) as the monohydrate salt. The mp was 205-206 !C. Even after 24 h drying at 100 !C under vacuum, the hydrate salt remained intact. Anal. (C15H20ClNO2aH2O) C,H. DOSAGE: unknown. DURATION: unknown, EXTENTIONS AND COMMENTARY: The evaluation of this compound is not yet complete. An initial trial at the 2 milligram level showed neither central action, nor toxicity. It could be guessed from the activity of the two-carbon counterpart, that an active level will be found in the tens of milligrams area. But, as of the moment, this level is not known to anyone, anywhere, because no one has yet defined it. And when the potency is finally found out, the nature of the activity will also have been found out, all the result of a magical interaction of a virgin compound with a virgin psyche. At the immediate moment, the nature of G-N is not only unknown, it has not yet even been sculpted. There can be no more exciting area of research than this, anywhere in the sentient world. #87 HOT-2; 2,5-DIMETHOXY-4-ETHYLTHIO-N-HYDROXYPHENETHYLAMINE SYNTHESIS: A solution of 5.50 g 2,5-dimethoxy-4-ethylthio-'-nitrostyrene (see under 2C-T-2 for its preparation) was made in 80 mL boiling anhydrous THF. On cooling, there was some separation of a fine crystalline phase, which was kept dispersed by continuous stirring. Under an inert atmosphere there was added 3.5 mL of a 10 M borane dimethylsulfide complex, followed by 0.5 g sodium borohydride as a solid. There was a slight exothermic response, and the color slowly faded. Stirring was continued for a week. There was then added 40 mL H2O and 20 mL concentrated HCl, and the reaction mixture heated on the steam bath for 15 minutes, with the THF at reflux. After cooling again to room temperature, all was poured into 1 L H2O and washed with 3x75 mL CH2Cl2, which removed all of the color but little of the product. The aqueous phase was made basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2. The extracts were pooled and the solvent removed under vacuum to give a residue of 3.88 g of an amber oil. This was dissolved in 30 mL IPA, acidified with concentrated HCL to a bright red on universal pH paper, and then diluted with 200 mL anhydrous Et2O. After a short period of time, crystals started to form. These were removed by filtration, washed with Et2O, and air dried to constant weight. Thus was obtained 2.86 g 2,5-dimethoxy-4-ethylthio-N-hydroxyphenethylamine hydrochloride (HOT-2) as off-white crystals, with a melting point of 122 !C with decomposition. Anal. (C12H20ClNO3 S) H; C: calcd, 49.05; found, 50.15, 49.90. DOSAGE: 10 - 18 mg. DURATION: 6 - 10 h. QUALITATIVE COMMENTS: (with 12 mg) Tastes OK. Some activity noticed in 30 minutes. Very smooth rise with no body load for next two hours. At that time I noted some visuals. Very pleasant. The bright spots in the painting over the fireplace seemed to be moving backwards (as if the clouds were moving in the painting). Upon concentrating on any item, there was perceptual movement with a little flowing aspect. The visuals were never all that strong, but could not be turned off during the peak. At hour three there was still some shimmering, and it was hard to focus when reading. Additionally, there was difficulty concentrating (some mental confusion). The material seemed to allow erotic actions; there was no problem about obtaining an erection. I ate very well, some crazy dips, as well as a fabulous cake. A very gentle down trend and I became close to baseline by 6 or 7 PM. I had no trouble driving. The dosage was good for me. I did not want more or less. (with 12 mg) Comes on smoothly, nicely. In 40 minutes I feel nice euphoria, feel home again. Then I begin to get uncomfortable feelings. Gets more and more uncomfortable, feel I am sitting on a big problem. Blood pressure, pulse, go up considerably. Have hard time communicating, lie down for a while, get insight that most important thing for me to do is learn to listen, pay attention to what is going on. I do this the rest of the day, at first with considerable difficulty, then easier and easier. Discomfort stays with me for several hours, and although I get more comfortable towards the end of the day, I am never animated or euphoric. I feel very humbled, that I have a great deal to work out in my life. The next day I find myself very strong and empowered. I see that all I have to do is let things be as they are! This feels marvelous, and a whole new way to be Q much more relaxed, accepting, being in the moment. No more axes to grind. I can be free. (with 18 mg) I found myself with complete energy. I was completely centered with an absolute minimum of the dark edges that so often appear as components of these experiences. The ease of talking was remarkable. There was some blood-pressure run-up in the early part of the day, but that quickly returned to normal. I would repeat without hesitation. EXTENSIONS AND COMMENTARY: Again, a case of where the potency range of the Rhot,S or hydroxylated compound (HOT-2, 10 to 18 milligrams) is very similar to that of the non-hydroxylated prototype (2C-T-2, 12-25 milligrams). It seems to be a well tolerated, and generally pleasant material, with a mixture of sensory as well as insightful aspects. Something for everyone. #88 HOT-7; 2,5-DIMETHOXY-N-HYDROXY-4-(n)-PROPYLTHIOPHENETHYLAMINE SYNTHESIS: A well-stirred solution of 1.77 g 2,5-dimethoxy-'-nitro-4-(n-propylthio)styrene (see under 2C-T-7 for its preparation) in 20 mL anhydrous THF was placed in an He atmosphere and treated with 1.5 mL of 10 M borane-dimethyl sulfide complex. This was followed by the addition of 0.2 g sodium borohydride, and the stirring was continued at room temperature for a week. The volatiles were removed under vacuum, and the residue was treated with 20 mL dilute HCl and heated on the steam bath for 30 min. The cooled yellow solution set up as solids. The addition of H2O was followed by sufficient K2CO3 to make the aqueous phase basic. All efforts to work with an acidified aqueous phase resulted in terrible emulsions. The basic phase was extracted with 3x75 mL CH2Cl2, and the pooled extracts washed with H2O, then stripped of solvent under vacuum. The residual yellow oil was dissolved in 20 mL IPA, neutralized with 15 drops of concentrated HCl, and then diluted with 50 mL anhydrous Et2O. After a few minutes stirring, a white crystalline solid separated. This was removed by filtration, washed with Et2O, and air dried to constant weight to provide 0.83 g of 2,5-dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine hydrochloride (HOT-7). DOSAGE: 15 - 25 mg. DURATION: 6 - 8 h. QUALITATIVE COMMENTS: (with 15 mg) I am lightheaded, and maybe a little tipsy. I am well centered, but I donUt want to go outside and meet people. Shades of alcohol woozy. The effects were going already by the fifth hour and were gone by the seventh hour. I would call it smoothly stoning. (with 22 mg) The transition into the effects was a bit difficult, with a faint awareness in the tummy. But by the second hour it was quite psychedelic, and the body was not thought of again, except in terms of sexual fooling around. Very rich in eyes-closed imagery, and very good for interpretive and conceptual thinking. But the eyes-open visuals were not as much as they might have been. At the seventh hour, drifted into an easy sleep. (with 22 mg) The experience was very positive, but at each turn there seemed to be a bit of sadness. Was it a complete plus three experience? Not quite. But it didnUt miss by much. The erotic explorations somehow just failed to knit by the thinnest of margins. It was a truly almost-magnificent experience. EXTENSIONS AND COMMENTARY: There is a working hypothesis that has been growing in substance over the last few years in this strange and marvelous area of psychedelic drugs. It all was an outgrowth of the rather remarkable coincidence that I had mentioned in the discussion that followed MDOH. There, an assay of what was thought to be MDOH gave a measure of activity that was substantially identical to MDA, and it was later found out that the material had decomposed to form MDA. So, MDA was in essence rediscovered. But when the true, valid, and undecomposed sample of MDOH was actually in hand, and assayed in its own rights, it was found to have a potency that really was the same as MDA. So, the working hypothesis goes something like this: AN N-HYDROXY AMINE HAS APPROXIMATELY THE SAME POTENCY AND THE SAME ACTION AS ITS N-HYDROGEN COUNTERPART. Maybe the N-hydroxy compound reduces to the N-H material in the body, and the latter is the intrinsically active agent. Maybe the N-H material oxidizes to the N-hydroxy material in the body, and the latter is the intrinsically active agent. Either direction is reasonable, and there is precedent for each. The equivalence of MDA and MDOH was the first suggestion of this. And I have made a number of NH vs. NOH challenges of this hypothesis. The interesting 2C-T-X series has provided a number of amines that are amenable to N-hydroxylation, and this is the first of them. And, after all, if you put a hydroxy (HO) group on a thio material (T), you have a HOT compound. So, as far as nomenclature is concerned, the family of N-hydroxy analogues of N-H amines is known as the HOT family. How does HOT-7 compare with 2C-T-7? They are almost identical. The same range of dose (centering on 20 milligrams) and if anything, perhaps slightly less long lived. Lets try some other N-hydroxys! #89 HOT-17; 2,5-DIMETHOXY-4-(s)-BUTYLTHIO-N-HYDROXYPHENETHYLAMINE SYNTHESIS: To a well-stirred solution of 6.08 g 2,5-dimethoxy-4-(s)-butylthio-'-nitrostyrene (see under 2C-T-17 for its preparation) in 80 mL anhydrous THF under a He atmosphere, there was added 3.5 mL 10 M borane dimethylsulfide complex, followed by 0.5 g of sodium borohydride. As the stirring continued, the slightly exothermic reaction slowly faded from bright yellow to pale yellow, and eventually (after three days stirring) it was substantially colorless. There was then added 80 mL of 3 N HCl and the mixture heated on the steam bath for 1 h, and then allowed to return to room temperature. An additional 600 mL H2O was added (there was a combination of crystals and globby chunks in the aqueous phase) and this was then extracted with 3x75 mL CH2Cl2. The color went completely into the organic phase. This was washed with 2x50 mL aqueous K2CO3, yielding a rusty-red colored CH2Cl2 solution, which on removal of the solvent, yielded 4.5 g of a red oil. A side effort to make the sulfate salt at this stage with H2O and a little H2SO4, indeed gave solids, but all of the color remained in the sulfate salt. The red oil was dissolved in 45 mL IPA and neutralized with concentrated HCl to bright red, not yellow, on universal pH paper. The addition of 350 mL anhydrous Et2O instituted the slow precipitation of white crystals. After filtering and air drying, there was obtained 1.32 g 2,5-dimethoxy-4-(s)-butylthio-N-hydroxyphenethylamine hydrochloride (HOT-17). The aqueous phase from above was just neutralized with 25% NaOH (cloudy, slightly pink color) and then made basic with K2CO3 (the color becomes green). This was extracted with 3x75 mL CH2Cl2, the extracts pooled, and the solvent removed to yield 0.5 g of a white oil. This was dissolved in 5 mL IPA, neutralized with concentrated HCl, and diluted with a equal volume of Et2O. An additional 0.36 g of product was thus obtained. DOSAGE: 70 - 120 mg. DURATION : 12 - 18 h. QUALITATIVE COMMENTS: (with 70 mg) There was a light feeling, a little off-the-ground feeling, which made walking about a most pleasant experience. No distortion of the senses. And there was no sense of the beginning of a drop of any kind until about the eighth hour. Sleeping was a bit tricky but it worked out OK (at the twelfth hour of the experience). A completely valid ++. (with 120 mg) HOT-17 has an unbelievably GRIM taste Q not bitter, but simply evil. There is a steady and inexorable climb for three hours to a sound and rolling plus three. There was absolutely no body difficulty, but there was still something going on upstairs well into the next day. Writing was surprisingly easy; I was completely content with the day, and would be interested in exploring it under a variety of circumstances. (with 120 mg) This is my first time with this material. It is 4:45 PM. Small nudge at 30 minutes, but not too real. At one hour, threshold, quite real. 6:15 to a +1. By 7:25, +3 about. 7:45, no doubt +3. Possibly still climbing; I hope so. No body discomfort at all, no apparent body push. This aspect of it is similar to the easy body of the HOT-2. However, it's at times like these that I reflect on just exactly how hard-headed we two are. I mean, +3 is no longer the out-of-body, nearly loss of center state it used to be, four years ago. The question intrudes: would a novice experience this as a very scary, ego-disintegrating kind of experiment, or not? Silly question which answers itself. Yes, of course. At 3 hours, aware of some mild time-distortion. More a tendency to not think in terms of clock-time, than actual distortion. The mind lazy when attempting to keep track of clock time. Feel it would be quite easy and pleasant to continue writing. The energy could very well go in that direction. However, the idea of the erotic is also quite agreeable. This is, so far, a good-humored Buddha area of the self. EXTENSIONS AND COMMENTARY: Two virtues sought by some users of psychedelic drugs are high intensity and brief action. They want a quicky. Something that is really effective for a short period of time, then lets you quickly return to baseline, and presumably back to the real world out there. Intensity is often (but not always) regulated by dose. The pharmacological property of dose-dependency applies to many of these drugs, in that the more you take, the more you get. If you want more intensity, take a second pill. And often, you get a longer duration as an added property. But it is instructive to inquire into the rationale that promotes brevity as a virtue. I believe that it says something concerning the reasons for using a psychedelic drug. A trade off between learning and entertainment. Or between the achieving of something and the appearance of achieving something. Or, in the concepts of the classics, between substance and image. In a word, many people truly believe that they cannot afford the time or energy required for a deep search into themselves. One has to make a living, one has to maintain a social life, one has a multitude of obligations that truly consume the oh-so-few hours in the day. I simply cannot afford to take a day off just to indulge myself in such-and-such (choose one: digging to the bottom of a complex concept, giving my energies to those whom I can help, to search out my inner strengths and weaknesses) so instead I shall simply do such-and-such (choose one: read the book review, go to church on Sunday morning, use a short-acting psychedelic). The world is too much with us. This may be a bit harsh, but there is some merit to it. HOT-17 is by no means a particularly potent compound. The hundred milligram area actually has been the kiss of death to several materials, as it is often at these levels that some physical concerns become evident. And it certainly is not a short lived compound. But, as has been so often the case, the long lived materials have proven to be the most memorable, in that once the entertainment aspect of the experience is past you, there is time for dipping deeply into the rich areas of the thought process, and the working through of ideas and concepts that are easily available. And when this access is coupled to the capability of talking and writing, then a rewarding experience is often the result. As with the parent compound, 2C-T-17 itself, the presence of an asym-metric carbon atom out there on the (s)-butyl side chain will allow the separation of HOT-17 into two components which will be different and distinct in their actions. The activity of the racemic mixture often is an amalgamation of both sets of properties, and the separate assay of each component can often result in a fascinating and unexpected fractionation of these properties.