AMINOPROPYL)-5,8-DIMETHOXYTETRALIN

 

SYNTHESIS: A solution of 1,4-dimethoxy-5,6,7,8-tetrahydro-beta-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 deg 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 deg C. Anal. (C16H19NO4) C,H.

 

A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He, to 0 deg 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 deg 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 deg 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 `cosmic') 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 "shrubbery" 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 deg 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 deg 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 deg 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 deg 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 didn't 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 deg 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 deg C. Recrystallization from MeOH gave a gold-colored product with a mp of 119-120 deg C. Anal. (C15H15NO4) C,H,N.

 

A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He, to 0 deg 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 deg 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 deg 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 deg C. Even after 24 h drying at 100 deg 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-beta-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 deg 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 "hot," 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-beta-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 don't 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 didn't 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-beta-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.

 

#90 IDNNA; 2,5-DIMETHOXY-N,N-DIMETHYL-4-IODOAMPHETAMINE

 

SYNTHESIS: To a stirred solution of 0.4 g 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in 12 mL MeOH containing 4 mL of a 40% formaldehyde solution there was added 1 g sodium cyanoborohydride. The pH was kept at about 6 by the occasional addition of HCl. When the pH was stable (about 48 h) the reaction mixture was poured into 250 mL H2O and made strongly basic by the addition of aqueous NaOH. This was extracted with 3x75 mL CH2Cl2, the extracts pooled, and extracted with 2x75 mL dilute H2SO4, and the pooled acidic extracts again made basic and again extracted with CH2Cl2. The solvent was removed under vacuum to give 0.38 g of a colorless oil. This was dissolved in 2 mL IPA and treated with a solution of 0.13 g oxalic acid dihydrate in 1.5 mL warm IPA, and then anhydrous Et2O was added dropwise until a turbidity persisted. Slowly a granular white solid appeared, which was filtered off, Et2O washed, and air dried to give 0.38 g of 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine oxalate (IDNNA) with a mp of 145-146 deg C. Anal. (C15H22INO6) C,H. The hydrochloride salt of this base proved to be hygroscopic.

 

DOSAGE: greater than 2.6 mg.

 

DURATION: unknown.

 

EXTENSIONS AND COMMENTARY: This base, if it were given a code name based upon its substituents arranged in their proper alphabetical order, would have to be called something like DNDIA, which is quite unpronounceable. But by a rearrangement of these terms, one can achieve IDNNA (Iodo-Dimethoxy-N,N-dimethyl-Amphetamine) which has a nice lilt to it.

 

One of the major goals of research in nuclear medicine is a drug that can be used to demonstrate the brain blood flow pattern. To do this job, a drug should demonstrate four properties. First, it must carry a radioactive isotope that is a positron emitter (best, a fluorine or an iodine atom, for use with the positron camera) that can be put onto the molecule quickly, synthetically, and which will stay on the molecule, metabolically. Second, as to brain entry, the drug should be rapidly and extensively taken up by brain tissue, without being selectively absorbed or concentrated at any specific sites. In other words, it should go where the blood goes. Thirdly, the absorption should be strong enough that it will stay in the brain, and not be washed out quickly. This allows time to both locate and count the radioactivity that was carried in there. And lastly, the drug must be without pharmacological action.

 

IDNNA looked like a promising candidate when tried with a radioactive iodine label, and there was quite a flurry of interest in using it both as an ex-perimental drug, and as a prototype material for the synthesis of structural variants. It went in quickly, extensively and quite diffusely, and it stayed in for a long time.

 

But was it pharmacologically active? Here one finds a tricky road to walk. The animal toxicity and behavioral properties can be determined in a straightforward manner. Inject increasing amounts into an experimental animal and observe him closely. IDNNA was quite inert. But, it is a very close analogue to the extremely potent psychedelic DOI, and it is widely admitted that animal assays are of no use in trying to determine this specific pharmacological property. So, a quiet human assay was called for. Since it did indeed go into the brain of experimental animals, it could quite likely go into the brain of man. In fact, that would be a needed property if the drug were to ever become useful as a diagnostic tool.

 

It was assayed up to levels where DOI would have been active, and no activity was found. So one could state that it had none of the psychedelic properties of DOI at levels where DOI would be active (this, at 2.6 milligrams orally). But you don't assay much higher, because sooner or later, something might indeed show up. So it can be honestly said, IDNNA is less active than DOI itself, in man. Let's wave our hands a bit, and make our statement with aggressive confidence. IDNNA has shown no activity in the human CNS at any level that has been evaluated. This sounds pretty good. Just don't go too far up there, and don't look too carefully. This is not as unscrupulous as it might sound since, in practical terms, the extremely high specific activities of the radioactive 122I that would be used, would dictate that only an extremely small amount of the drug would be required. One would be dealing, not with milligram quantities, but with microgram quantities, or less.

 

Some fifteen close analogues of IDNNA were prepared, to see if any had a better balance of biological properties. A valuable intermediate was an iodinated ketone that could be used either to synthesize IDNNA itself or, if it were to be made radio-labelled, it would allow the preparation of any desired radioactive analogue in a single synthetic step. The iodination of p-dimethoxybenzene with iodine monochloride in acetic acid gave 2,5-diiodo-1,4-dimethoxybenzene as white crystals from acetonitrile, with a mp of 167-168 deg C. Anal. (C8H8I2O2) C,H. Treatment of this with an equivalent of butyllithium in ether, followed with N-methyl formanilide, gave 2,5-dimethoxy-4-iodobenzaldehyde as pale yellow crystals from ethanol, with a mp of 136-137 deg C. Anal. (C9H9IO3) C,H. This, in solution in nitroethane with a small amount of anhydrous ammonium acetate, gave the nitrostyrene 1-(2,5-dimethoxy-4-iodophenyl)-2-nitropropene as gold-colored crystals from methanol, mp 119-120 deg C. Anal. (C11H12INO4) C,H. This was smoothly reduced with ele-mental iron in acetic acid to give 2,5-dimethoxy-4-iodophenylacetone as white crystals from methylcyclopentane. These melted at 62-63 deg C and were both spec-troscopically and analytically correct. Anal. (C11H13IO3) C,H.

 

This intermediate, when reductively aminated with dimethylamine, gives IDNNA identical in all respects to the product from the dimethylation of DOI above. But it has also been reacted with 131I NaI in acetic acid at 140 deg C for 10 min, giving the radioactive compound by exchange, and this was reductively aminated with over a dozen amines to give radioactive products for animal assay. There was produced in this way, 2,5-dimethoxy-4-iodo-N-alkyl-amphetamine where the alkyl group was methyl, isopropyl, cyclopropylmethyl, hexyl, dodecyl, benzyl, cyanomethyl, and 3-(dimethylaminopropyl). Several dialkyl homologue were made, with the alkyl groups being dimethyl (IDNNA itself), diethyl, isopropyl-methyl, and benzyl-methyl. These specific homologues and analogues are tallied in the index, but a number of other things, such as hydrazine or hydroxylamine derivatives, were either too impure or made in amounts too small to be valid, and they are ignored.

 

The diethyl compound without the iodine is 2,5-dimethoxy-N,N-diethylamphetamine, which was prepared by the reductive alkylation of DMA with acetaldehyde and sodium cyanoborohydride. This product, DEDMA, was a clear white oil, bp 82-92 deg C at 0.15 mm/Hg which did not form a crystalline hydrochloride. An interesting measure of just how different these N,N-dialkylated homologues can be from the psychedelic primary amines, pharmacologically, can be seen in the published report that the beta-hydroxy derivative of DEDMA is an antitussive, with a potency the same as codeine.

 

None of these many iodinated IDNNA analogues showed themselves to be superior to IDNNA itself, in the rat model, and none of them have been tasted for their psychedelic potential in man.      

 

 

 

#91 IM; ISOMESCALINE; 2,3,4-TRIMETHOXYPHENETHYLAMINE

 

SYNTHESIS: A solution of 8.0 g 2,3,4-trimethoxybenzaldehyde in 125 mL nitromethane containing 1.4 g anhydrous ammonium acetate was held at reflux for 1.5 h. The conversion of the aldehyde to the nitrostyrene was optimum at this time, with a minimum development of a slow-moving spot as seen by thin layer chromatography on silica gel plates using CHCl3 as a developing solvent; the Rf of the aldehyde was 0.31 and the Rf of the nitrostyrene was 0.61. The excess nitromethane was removed under vacuum, and the residue was dissolved in 20 mL hot MeOH. On cooling, the yellow crystals that formed were removed by filtration, washed with cold MeOH and air dried yielding 4.7 g yellow crystals of 2,3,4-trimethoxy-beta-nitrostyrene, with a mp of 73-74 deg C. From the mother liquors, a second crop of 1.2 g was obtained.

 

A solution of 4.0 g LAH in 80 mL THF under He was cooled to 0 deg C and vigorously stirred. There was added, dropwise, 2.7 mL of 100% H2SO4, followed by a solution of 4.7 g 2,3,4-trimethoxy-beta-nitrostyrene in 40 mL anhydrous THF. The mixture was stirred at 0 deg C for 1 h, at room temperature for 1 h, and then brought briefly to a reflux on the steam bath. After cooling again, the excess hydride was destroyed with 4.7 mL H2O in THF, followed by the addition of 18.8 mL 15% NaOH which was sufficient to convert the solids to a white and granular form. These were removed by filtration, the filter cake washed with THF, the mother liquor and filtrates combined, and the solvent removed under vacuum. The residue was added to dilute H2SO4, and washed with 2x75 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 2x50 mL CH2Cl2. The solvent was removed from these pooled extracts and the amber-colored residue distilled at 95-100 deg C at 0.3 mm/Hg to provide 2.8 g of 2,3,4-trimethoxyphenethylamine as a white oil. This was dissolved in 20 mL IPA, neutralized with about 1 mL concentrated HCl, and diluted with 60 mL anhydrous Et2O. After filtering, Et2O-washing, and air drying, there was obtained 3.2 g of 2,3,4-trimethoxyphenethylamine hydrochloride (IM) as a white crystalline product.

 

DOSAGE: greater than 400 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 300 mg) No effects whatsoever.

 

(with 400 mg) Maybe a slight tingle at the hour-and-a-half point. Maybe not. Certainly nothing an hour later. Put this down as being without action.

 

EXTENSIONS AND COMMENTARY: Some fifty years ago this material was given the name "reciprocal mescaline" in that it was believed to exacerbate the clinical symptoms in schizophrenic patients. In the original report, one finds: RThus we have discovered an extremely remarkable dependency of the intoxicating action upon the position of the three methoxy groups. Mescaline, the 3,4,5-trimethoxy-beta-phenethylamine, produces in the normal subject a much stronger over-all intoxication than in the schizophrenic patient, whereas 2,3,4-trimethoxy-beta-phenethylamine has quite the opposite effect. It has little action in healthy individuals, being almost without intoxicating properties, but it is very potent in the schizophrenic. The metabolic conversion products of the "reciprocal" mescaline will be further studied as soon as the study of the metabolism of the proper mescaline is complete.

 

This is a pretty rich offering, and one that the present medical community has no qualms about discarding. At the bookkeeping level, the promised further studies have never appeared, so all may be forgotten as far as potential new discoveries might be concerned.

 

One recent related study has been reported, tying together isomescaline and schizophrenia. Through the use of radioactive labelling, the extent of demethylation (the metabolic removal of the methyl groups from the methoxyls) was determined in both schizophrenic patients and normal subjects. When there was a loading of the person with methionine (an amino acid that is the principal source of the body's methyl groups), the schizophrenics appeared to show a lesser amount of demethylation.

 

But might either of these two observations lead to a diagnostic test for schizophrenia? At the present time, the conventional thinking is that this probably cannot be. The illness has such social and genetic contributions, that no simple measure of a response to an almost-psychedelic, or minor shift of some urinary metabolite pattern could possibly be believed. No independent confirmation of these properties has been reported. But maybe these findings are valid. A major problem in following these leads does not involve any complex research protocols. What must be addressed are the present regulatory restrictions and the Federal law structure. And these are formidable obstacles.          

 

#92 IP; ISOPROSCALINE; 3,5-DIMETHOXY-4-(i)-PROPOXYPHENETHYLAMINE

 

SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under ESCALINE for its preparation) and 13.6 g isopropyl iodide in 50 mL dry acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and held at reflux on the steam bath. After 6 h another 5 mL of isopropyl iodide was added, and refluxing continued for an additional 12 h. The mixture was filtered and the solids washed with acetone. The mother liquor and washes were stripped of solvent under vacuum, The residue was taken up in dilute HCl, and extracted with 3x100 mL CH2Cl2. The pooled extracts (they were quite deeply yellow colored) were washed with 2x75 mL 5% NaOH, and finally once with dilute HCl. Removal of the solvent under vacuum yielded 9.8 g of an amber oil, which on distillation at 125-135 deg C at 0.3 mm/Hg provided 6.0 g of 3,5-dimethoxy-4-(i)-propoxyphenylacetonitrile as a pale yellow oil. A pure reference sample is a white solid with a mp of 33-34 deg C. Anal. (C13H17NO3) C,H,N.

 

A solution of AH was prepared by the cautious addition of 0.84 mL of 100% H2SO4 to 32 mL of 1.0 M LAH in THF, which was being vigorously stirred under He at ice-bath temperature. A solution of 5.93 g of 3,5-dimethoxy-4-(i)-propoxyphenylacetonitrile in 10 mL anhydrous THF was added dropwise. Stirring was continued for 30 min, then the reaction mixture was brought up to reflux on the steam bath for another 30 min. After cooling again to room temperature, 5 mL IPA was added to destroy the excess hydride, followed by about 10 mL of 15% NaOH, sufficient to make the aluminum salts loose, white, and filterable. The reaction mixture was filtered, the filter cake washed with IPA, the mother liquor and washes combined, and the solvent removed under vacuum. The residue (7.0 g of an amber oil) was dissolved in dilute H2SO4 and washed with 3x75 mL CH2Cl2. The aqueous phase was made basic with aqueous NaOH, and the product extracted with 3x75 mL CH2Cl2. The extracts were evaporated to a residue under vacuum, and this was distilled at 125-140 deg C at 0.3 mm/Hg yielding 3.7 g of a colorless oil. This was dissolved in 15 mL IPA, neutralized with 50 drops of concentrated HCl which allowed the deposition of a white crystalline product. Dilution with anhydrous Et2O and filtration gave 3.7 g. of 3,5-dimethoxy-4-(i)-propoxyphenethylamine hydrochloride (IP) with a mp of 163-164 deg C. Anal. (C13H22ClNO3) C,H,N. The catalytic hydrogenation process for reducing the nitrile that gives rise to escaline, also works with this material.

 

DOSAGE: 40 - 80 mg.

 

DURATION: 10 - 16 h.

 

QUALITATIVE COMMENTS: (with 75 mg) Starts slowly. I develop some queasiness, turning into nausea. Feels good to lie down and let go, but the uneasiness remains. Just beginning to break through in 2 hours. But the occasional sense of relief, the breaking into the open, were transient as new sources of discomfort were always being dredged up. Then for some reason I chose to dance. Letting go to dancing, a marvelous ecstatic experience, flowing with and being the energy, body feeling completely free. Noticing how this letting go got one completely out of the feeling of unease, as though attention simply needs to be put elsewhere. Comedown was very slow, gentle, euphoric; a very signicant experience. Sleep that night was impossible, but felt good to simply release to the feelings. Keeping mind still, no thinking, just allowing feelings to go where they wished, became more and more ecstatic. Tremendous feeling of confidence in life and the life process. Complete sense of resolution.

 

(with 80 mg) It took about two hours for the body to settle down. Emotions were true and well felt, a fact that is an all-important thing to me as it probably is to everyone else I know in this kind of exploration. Any sense that there is a dulling of the feeling and emotional area of the self is a negative, to be watched and noted as are other things such as disturbed sleep, unpleasant dreams, or irritability or depression the next day. I was interacting with others with a great deal of intensity. People found themselves wandering inside and out, listening to music, stirring soup, eating a bit and enjoying eating, talking, laughing a great deal, and being silent in great contentment. It's not a very silent material, though. Talking is too enjoyable. There was a slight descent noted at 6-7 hours, but very gentle and smooth. Slow and pleasant descent until about 12th hour, when sleep was attempted. Next day, everyone slightly irritable but good mood anyway. The next night I slept deeply and well, and awoke whole and in excellent mood.

 

EXTENSIONS AND COMMENTARY: These two excerpts give the color and complexity of IP. It has proven to be a completely fascinating phenethylamine. And, as with all the phenethylamines, there is an amphetamine that corresponds to it. This would be 3,5-dimethoxy-4-isopropoxyamphetamine, or 3C-IP. The prepa-ration of it would require access through the O-isopropoxylation product with syringaldehyde, followed by nitrostyrene formation with nitroethane, followed by reduction probably with lithium aluminum hydride. It has not been synthesized, as far as I know, and so it has probably not been evaluated in man. What would be the active level? It would probably be more potent than IP, but I would guess not by much. Maybe in the 30 milligram area.

 

A moment's aside for a couple of the words that are so much a part of the chemist's jargon. Room temperature, as used above, means the natural temperature that something comes to if it is put on the table and is neither heated nor cooled. The phrase, I discovered during my year at Gif, is completely un-understandable in French. A room has no temperature. Only things in rooms have temperatures. Their expression is more exact. The object achieves, in the French terminology, a temperature normale d'interieur, or about 15 to 16 deg C. But in common laboratory parlance it has become the temperature d'ambiance.

 

And one finds the prefix "iso" used everywhere. Considerable care should be taken in the two different uses of the prefix "iso" in the nomenclature with the mescaline analogues. In general, the term "iso" means the other one of two possibilities. If you are allowed to paint a house only with green paint or red paint, and green is the color you actually use, then red could be called iso-green. With isoproscaline (here) there is a rearranging of the propyl group on the 4-oxygen of mescaline. It has been replaced with its branched analogue, the other of two possibilities, the isopropyl group. Everything is still with the 3,4,5-orientation on the benzene ring. However, with IM (isomescaline) there is a rearrangement of substitution pattern on the benzene ring, with the repositioning of the trimethoxyl substitution pattern from the 3,4,5- arrangement to the 2,3,4- arrangement. It has been the side-chain that has taken the other of two possible positions. The term "iso" must always be interpreted in precise context.     

 

 

 

#93 IRIS; 5-ETHOXY-2-METHOXY-4-METHYLAMPHETAMINE

 

SYNTHESIS: To a solution of 9.5 g flaked KOH (10% excess) in 500 mL 95% EtOH there was added 20.4 g 4-methoxy-2-methylphenol (see under 2C-D for its preparation). This was followed with 23.5 g ethyl iodide, and the mixture was held at reflux overnight. The solvent was removed under vacuum and the residue suspended in 250 mL H2O. This was made strongly basic with NaOH and extracted with 3x50 mL CH2Cl2. Removal of the solvent gave 15.75 g of 2-ethoxy-5-methoxytoluene as an amber oil, which was used in the following step without further purification. Acidification of the aqueous phase followed by CH2Cl2 extraction gave, after removal of the solvent, crude recovered starting phenol as a dark brown crystalline solid. The reasonably pure phenol was best isolated by sequential extractions with portions of 80 deg C H2O which, on cooling, deposited the phenol as white crystals.

 

A mixture of 38 mL POCl3 and 43 mL N-methylformanilide was allowed to incubate for 1 h and then there was added to it 15.7 g 2-ethoxy-5-methoxytoluene. This was heated in the steam bath for 2 h, then poured into 1 L H2O and allowed to stir overnight. The solids that formed were removed by filtration and H2O washed, giving 20.7 g of a crude, amber product. This was extracted with 2x150 mL boiling hexane which gave crystals on cooling. These were filtered and hexane washed, giving 12.85 g of 5-ethoxy-2-methoxy-4-methylbenzaldehyde as pale cream-colored solids with a mp of 75-76 deg C. Recrystallization of an analytical sample from EtOH two times gave a product with a white color, and a mp of 81-82 deg C.

 

To a solution of 11.35 g 5-ethoxy-2-methoxy-4-methylbenzaldehyde in 48 mL glacial acetic acid containing 4 g anhydrous ammonium acetate there was added 10 mL nitroethane, and the mixture heated on the steam bath for 2 h. Standing at room temperature overnight allowed a heavy crop of brilliant crystals to deposit. These were removed by filtration, washed cautiously with acetic acid, and air dried to give 8.6 g 1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene with a mp of 118-120 deg C. Recrystallization of all from 200 mL boiling MeOH gave 8.3 g of lustrous crystals with a mp of 121-122 deg C.

 

To a gently refluxing suspension of 6.4 g LAH in 500 mL anhydrous Et2O under a He atmosphere, there was added 8.1 g 1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene by allowing the condensing ether to drip into a shunted Soxhlet thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene 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 400 mL H2O containing 40 g H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 160 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 3x50 mL CH2Cl2. Evaporation of the solvent under vacuum produced an oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. There appeared 5-ethoxy-2-methoxy-4-methylamphetamine hydrochloride (IRIS) as fine white crystals. These weighed, after filtration, Et2O washing, and air drying to constant weight, 5.3 g and had a mp of 192-193 deg C. Recrystallization of an analytical sample from boiling CH3CN gave lustrous crystals with a mp of 196-197 deg C with decomposition.

 

DOSAGE: greater than 9 mg.

 

DURATION: unknown.

 

QUALITATIVE COMMENTS: (with 7.5 mg) At about three hours I felt that I was at threshold, but an hour later there was nothing.

 

(with 9 mg) Maybe a little light headed? Maybe not. Little effect if any.

 

EXTENSIONS AND COMMENTARY: This is one of the ten Classic Ladies, the ten possible homologues of DOM, which I had discussed under ARIADNE (the first of the Ladies). The active level is unknown, but it is higher than 9 milligrams (the highest dose tried) and since DOM itself would have been smashingly active at this level, it is obvious that IRIS is a homologue with decreased potency.

 

This lack of activity brings up a fascinating point. I have referred to a drug's action on the mind, quite frequently in these notes, with the phrase "reasonably complex." By that, I do not mean that a drug's action simply shows many facets, and if these were to be tallied, the drug-mind interaction would become clear. There is quite a bit of importance intrinsically implied by the term, complex. Simple things, as we have come to appreciate and depend upon them in our day-to-day living, can have simple explanations. By this, I mean explanations that are both completely satisfactory and satisfactorily complete. Answers that have all the earmarks of being correct. What is the sum of two plus three, you ask? Let's try five. And for most of our needs, five is both factual and complete.

 

But some years ago, a mathematician named Gödel devised a proof for a theorem that anything that is reasonably complex cannot enjoy this luxury (I believe he used the word "interesting" rather than reasonably complex). If your collection of information is factual, it cannot be entirely complete. And if it is complete, it cannot be entirely factual. In short, we will never know, we cannot ever know, every fact that constitutes an explanation of something. A complete book of knowledge must contain errors, and an error-free book of knowledge must be incomplete.

 

There is a small warning light deep inside me that starts flashing any time I hear someone begin to advance an explanation of some reasonably complex phenomenon with an air of confidence that implies, "Here is how it works." What the speaker usually has is an intense familiarity with one particular discipline or specialty and the phenomenon is viewed through those eyes, often with the assurance that looking at it that way, intently enough and long enough, will reveal the complete explanation. And be attentive to the phrase, "We are not yet com-pletely sure of exactly how it works." What is really meant is, "We haven't the slightest idea of how it really works."

 

I must admit to some guilt in this matter, certainly as much as the next person. I am a chemist and I suspect that the way that the psychedelic drugs do their thing can eventually be understood through a comparison of the structures of the molecules that are active and those that are inactive. I put those that have methoxyl groups in pigeon hole #1, and those that are bicyclic into pigeon hole #2. And then, if pigeon hole #2 becomes more and more cluttered, I will subdivide the contents into pigeon hole #2A for bicyclics with heteroatoms and pigeon hole #2B for bicyclics without heteroatoms. The more information I can accumulate, the more pigeon holes I need.

 

But in the adjoining lab, there is a molecular biologist who feels that the eventual explanation for the action of the psychedelic drug will come from the analysis and understanding of the intimate geometry of the places in the brain where they act. These classification pigeon holes are called receptor sites. But they, too, can become more and more subdivided as they become cluttered. One reads of a new sub-sub type quite regularly in the literature. The favorite neurotransmitter of the moment, as far as the current thinking of how these marvelous drugs work, is serotonin, or 5-HT (for 5-hydroxytryptamine). There are 5-HT1 and 5-HT2A and 5-HT2B and (for all I know right now) 5-HT2C and 5-HT2D receptors, and I don't really think that either he or I have come much closer to understanding the mechanism of action.

 

And, since the mind is a reasonably complex system, Gödel has already informed us both that neither of us will be completely successful. Sometimes I feel that the pigeon hole approach to the classification of knowledge might actually limit our views of the problem. A Harvard Professor of Medicine recently noted: RWe must recognize for what it is, man's predilection for dividing things into tidy categories, irrespective of whether clarity is gained or lost thereby.

 

No. No one will ever have it all together. It is like sitting down in front of a jigsaw with a zillion zillion pieces spread all over the kitchen table. With diligent searching you will occasionally find a piece that matches another, but it rarely provides any insight into the final picture. That will remain a mystery, unless you had the chance to see the cover of the box in some other incarnation. But Oh my, what fun it is, whenever you do happen to find a new piece that fits!

 

This harangue is really a lengthy prelude to the story of putting an ethoxy group in place of a methoxy on the 2,5-dimethoxy skeleton of these psychedelic families. The making of IRIS was the first move in this direction, done back in 1976. One can have a pigeon hole that is named "Ethoxy In Place of Methoxy" and toss in there the names of perhaps twenty pairs of compounds, which differ from one another by just this feature. Yet when they are looked at from the potency point of view, there are some which show a decrease in potency (which is the case with IRIS and most of the Tweetios) and there are some which seem to maintain their potency (such as the TMA-2/MEM pair) and there are some where there is a distinct potency increase (the mescaline/escaline pair, for example).

 

What does one do to clarify the contents of this particular pigeon hole? The current fad would be to subdivide it into three subdivisions, maybe something like "Ethoxy in Place of Methoxy if 2- or 5-located" and "Ethoxy in Place of Methoxy if 4-located and other things 2,5" and "Ethoxy in Place of Methoxy if 4-located, and other things 3,5." The end point that soon becomes apparent, down the line, will be to have as many pigeon holes as compounds! And at the moment, this particular piece of the jigsaw puzzle doesn't seem to fit anywhere at all.

 

Perhaps both my neighboring molecular biologist and I are asking the wrong questions. I am looking at the molecules and asking, "What are they?" And he is following them and asking, "Where do they go?" And neither of us is fully attentive to the question, "What do they do?" It is so easy to replace the word "mind," in our inquiries, with the word "brain."

 

Yup. The operation of the mind can certainly be classified as a "reasonably complex" phenomenon. I prefer Gödel's term. The mind is without question an "interesting" phenomenon.

 

 

 

 #94 J; BDB; 2-AMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE;

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