C-T-4; 2,5-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE

SYNTHESIS: To a solution of 2.5 g of KOH pellets in 40 mL hot EtOH, there was added 5.4 g 2,5-dimethoxythiophenol (see under 2C-T-2 for its preparation) and 8.7 g isopropyliodide. White solids appeared in a few min, and the reaction mixture was heated on the steam bath overnight. This mixture was added to 200 mL H2O followed by additional aqueous NaOH to raise the pH to a deep purple-blue on universal pH paper. This was extracted with 3x75 mL CH2Cl2. The pooled extracts were stripped of solvent under vacuum, and the residue distilled at 100-110 deg C at 0.2 mm/Hg to yield 6.9 g of 2,5-dimethoxyphenyl isopropyl sulfide as a pale yellow oil. It has a very light, pleasant smell of apples.

A mixture of 4.8 g POCl3 and 4.5 g N-methylformanilide was stirred and allowed to stand at room temperature for 1 h To this claret-colored solution was added 3.0 g of 2,5-dimethoxyphenyl isopropyl sulfide, producing an exothermic reaction and immediate reddening. This was heated for 0.5 h on the steam bath, then quenched in 200 mL of warm H2O producing immediate crystals. Stirring was continued for a few min, and then the solids were removed by filtration, washed with H2O and sucked as dry as possible. When they were ground up under an equal weight of cold MeOH, refiltered and air dried, they gave 2.35 g of 2,5-dimethoxy-4-(i-propylthio)benzaldehyde as pale yellow solids (in some runs this was a pale lime-green color) with a mp of 89-90 deg C. A wasteful recrystallization from MeOH gave pale yellow crystals with a mp of 90 deg C sharp.

To a solution of 6.7 g 2,5-dimethoxy-(i-propylthio)benzaldehyde in 40 g of nitromethane there was added 0.10 g of anhydrous ammonium acetate, and the mixture was heated on the steam bath for 2 h. The excess reagent/solvent was removed under vacuum yielding 8.9 g of orange solids. This was recrystallized from 200 mL boiling MeOH providing 6.2 g of 2,5-dimethoxy-beta-nitro-4-(i-propyl-thio)styrene as lustrous golden orange platelets.

A solution of LAH (80 mL of a 1 M solution in THF) was cooled, under He, to 0 deg C with an external ice bath. With good stirring there was added 2.1 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 5.74 g 2,5-dimethoxy-beta-nitro-4-(i-propylthio)styrene as a solid, a bit at a time. After 15 min further stirring, the temperature was brought up to a gentle reflux on the steam bath for another 15 min, then allowed to stand at room temperature overnight. After cooling again to 0 deg C, the excess hydride was destroyed by the addition of 7 mL IPA followed by 6 mL 15% NaOH which was sufficent to give a white granular character. The reaction mixture was filtered and the filter cake washed with THF. The filtrate and washings were pooled, stripped of solvent under vacuum providing 3.9 g of a pale amber oil which was dissolved in 250 mL dilute H2SO4. This was washed with 3x75 mL CH2Cl2 which removed the residual yellow color. After making basic with 25% NaOH, the product was extracted with 3x75 mL CH2Cl2 and the solvent removed under vacuum to give 2.72 g of a residue which was distilled at 140-145 deg C at 0.2 mm/Hg to give 2.42 g of a clear white oil. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl. This gave a clear solution which, with good stirring, was diluted with 100 anhydrous Et2O to provide 2.40 g 2,5-dimethoxy-4-(i)-propyl-thiophenethylamine hydrochloride (2C-T-4) as white crystals.

DOSAGE: 8 - 20 mg.

DURATION: 12 - 18 h.

QUALITATIVE COMMENTS: (with 8 mg) Visual effects set in at about two hours. There was much color enhancement, particularly of green, and some flowing of colors. The bright impressionistic picture of the little girl, in the bathroom, was particularly good for the visuals to take over, especially when I was concentrating on urinating. The shadows in the large picture above the fireplace would change constantly. I could not either control or turn off these effects during the middle period (3-6 hours). From the physical point of view, something early in the experience simply didn't feel right. Both my lower legs tended to fall asleep, and this seemed to spread to my hands and lower arms. It was uncomfortable and although I was apprehensive at first it didn't get any worse with time so I ignored it. This is not one my favorite materials, and it takes too long to wear off. If I were to do it again I would settle for 4 or 5 milligrams. It may well cut out the extremity problem amd still allow for a pleasant experience.

(with 9 mg) An important characteristic of this experience was the sense of letting go and flowing with it. Just follow where it leads. This seemed to lead to a growing euphoria, a feeling of clearing out of body residues, and the handling of very impressive insights. My thinking continued to grow in clarity, visual perception was crystal clear, and it was a joy to simply look over the scenery, enjoy the beauty, enjoy the companionship, and ponder whatever came to mind. This clarity of body and mind lasted the rest of the evening with a wonderful feeling of peace and centeredness. I still felt a lot of push from the chemical at bed time, causing some tiredness, and allowing very little sleep. I kept working at what had taken place, all night, just to release the experience.

(with 14 mg) Very rational, benign, and good humored. The insight and calm common to the 2C-T's are present, with less of the push of body-energy which makes 2C-T-2 difficult for some people. There are no particular visuals, but then I tend to screen them out consistently, except in cases of mescaline and LSD and psilocybin, so I can't judge what others would experience in the visual area. The eyes-closed imagery is very good without being compelling. The decline is as gradual and gentle as the onset. I am fully capable of making phone calls and other normal stuff. Music is marvelous, and the body feels comfortable throughout.

(with 14 mg) Persistent cold feet, and an uncertain stomach when moving around. Brilliant color trails reminiscent of 2C-B. But a change is occurring and I can't talk myself out of it. There are dark corners. If I were with other people, this would bring out the worst in me, which can be pretty bad.

(with 19 mg) I was caught by the TV. Leonard Bernstein conducting West Side Story. I think I know every note. This was a 1985 rehearsal with the goofs and the sweat. And now Peter, Paul and Mary, grown older along with the songs we all sang. Where Have All the Flowers Gone Q and an audience of grown-older people singing Puff the Magic Dragon like earnest children and probably crying along with me. It is good to have lived through the 60's and not to be in them now. Now there's a new song about El Salvador and it's the battle all over again on a different field, but it will always be so, until and unless. Now, in the 80's, I don't get really angry anymore. I am more warrior than angry protester, and that's a much better way to be. In fact, I am quite happy to be where I am. I know a lot more about the game, and what it is, and why it is played, and I have a good idea about my part in it, and I like the part I've chosen.

(with 22 mg) The transition took place over three hours, an alert in 30 minutes followed by a slow and gentle climb. I found it difficult, not physically but mentally since I was for a while locked into the illogical and disconnected aspects of human experiences and expressions, particularly laws and pronouncements and unseeing prejudices, most of which I was picking up from reading the Sunday paper book reviews. As time went on, things became less pushy and I came to be at ease with very positive feelings about everything going on. No self-rejecting aspect at all. Sleep was excellent, but the next day things went slowly and I had to nap a bit. Next time, maybe 18 milligrams.

EXTENSIONS AND COMMENTARY: There are shades of the variability of the Alephs. Some observers are overwhelmed with colors and visual activity; others volunteer their absence. And a very wide range of dosages represented, from an estimated 4 or so milligrams for full effects, to something over 20 milligrams without any loss of control. That is an unusually wide lattitude of activity. And a rich variety of effects that might be experienced. The same wide range of effective dosages was also observed with the corresponding Tweetio. The 2-EtO-homologue of 2C-T-4 is 2-ethoxy-5-methoxy-4-(i)-propylthiophenethylamine, or 2CT4-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-(i-propylthio)benzaldehyde had a melting point of 43-44 deg C, the nitrostyrene intermediate a melting point of 77-79 deg C, and the final hydrochloride a melting point of 153.5-154 deg C. There were practically no differences between trials at 5 milligram increments within the 10 and 25 milligram range. Each produced a gentle plus two level of effect which lasted for some 10 hours. A code name of "tenderness" was felt to be appropriate, as there was a peaceful meditative inner receptiveness and clarity noted, with an honest connection felt with those who were present during the experience. Sleep was not comfortable.

I have heard 2C-T-4 referred to as T-4. There is a potent explosive used by terrorists called cyclotrimethylenetrinitramine, known by the code name RDX, or T-4. There is also a T-4 term that refers to thyroxine, an amino acid in the body. The drug 2C-T-4 is neither an explosive nor an amino acid, I am happy to say.

#42 gamma-2C-T-4; 2,6-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE)

SYNTHESIS: A stirred solution of 8.3 g 3,5-dimethoxy-1-chlorobenzene and 7.2 g isopropylsulfide in 100 mL anhydrous Et2O was cooled with an external ice bath, and then treated with 67 mL 1.5 M lithium diisopropylamide in hexane which was added over the course of 10 min. The reaction mixture was allowed to return to room temperature and the stirring was continued for 0.5 h. The mixture was poured into dilute H2SO4, the organic layer was separated, and the aqueous phase extracted with 3x75 mL EtOAc. The organic phases were combined, dried over anhydrous K2CO3, and the solvent removed under vacuum. The resulting 4.54 g of almost colorless oil was distilled at 85-95 deg C at 0.1 mm/Hg to give 4.2 g of 3,5-dimethoxyphenyl isopropyl sulfide as a colorless oil, showing a single spot on TLC with no indication of starting chlorobenzene. The product formed a picrate salt, but this had an unsatisfactory mp character (partly melting at 45-47 deg C, and then completely at about 80-90 deg C). The microanalysis for this picrate was low in the carbon value, although the hydrogen and nitrogen were excellent. Anal. (C17H19N3O9S) H,N; C: calcd, 46.25; found, 44.58, 44.45.

To a well-stirred solution of 4.1 g 3,5-dimethoxyphenyl isopropyl sulfide and 3.5 mL N,N,N',N'-tetramethylethylenediamine in 25 mL anhydrous Et2O that had been cooled to -78 deg C with a dry-ice/acetone bath, there was added 10 mL 2.5 M hexane solution of butyllithium. The mixture was allowed to return to room temperature, and there was added 3.5 mL DMF which caused the yellow color to progressively darken. The reaction mixture was poured into dilute H2SO4, the Et2O layer was separated, and the aqueous phase extracted with 3x75 mL EtOAc. The solvent was removed from the combined organic phases, and the residue distilled at 0.15 mm/Hg to give two fractions. One, boiling at 120-140 deg C, was 0.98 g of a pale yellow mobile liquid, which was part starting sulfide and part product aldehyde by TLC. The second cut, boiling at 160-180 deg C, was a viscous liquid, weighed 1.66 g, and was largely 2,6-dimethoxy-4-(i-propylthio)benzaldehyde. This formed a crystalline anil with 4-methoxyaniline (by fusing equimolar amounts of the two with a flame) which, after recrystallization from MeOH, gave fine yellow crystals with a mp of 87.5-89 deg C. Anal. (C19H23NO3S) C,H.

A solution of 0.8 g 2,6-dimethoxy-4-(i-propylthio)benzaldehde in 10 mL nitromethane was treated with 0.2 g anhydrous ammonium acetate and heated on the steam bath for 1 h. The excess reagent/solvent was removed under vacuum, and the residue spontaneously solidified. This was recrystallized from 5 mL MeOH to give 0.70 g 2,6-dimethoxy-beta-nitro-4-(i)-propylthiostyrene as a pale yellow fluffy solid, with a mp of 83-84.5 deg C. Anal. (C13H17NO4S) C,H.

A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under He to 0 deg C with an external ice bath. With good stirring there was added 0.54 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 0.54 g 2,6-dimethoxy-beta-nitro-4-(i)-propylthiostyrene in a small volume of anhydrous THF. The color was discharged immediately. After a few minutes further stirring, the temperature was brought up to a gentle reflux on the steam bath for about 10 min, and then all was cooled again to 0 deg C. The excess hydride was destroyed by the cautious addition of IPA followed by sufficent 15% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic. The reaction mixture was filtered, and the filter cake washed well with THF. The filtrate was stripped of solvent under vacuum and the residue dissolved in 100 mL of dilute H2SO4. This was washed with 2x50 mL CH2Cl2 (the washes were saved, see below), made basic with aqueous NaOH, and then extracted with 2x50 mL CH2Cl2. The residue remaining after the removal of the solvent was distilled at 130-140 deg C at 0.05 mm/Hg to give 0.11 g of a white oil. This was dissolved in 10 mL IPA, neutralized with 5 drops of concentrated HCl and diluted with 50 mL anhydrous Et2O. After filtration of the formed crystals, Et2O washing, and air drying, there was obtained 80 mg of 2,6-dimethoxy-4-(i)-propylthiophenethylamine hydrochloride (gamma-2C-T-4) as fine white crystals. The removal of the solvent from the CH2Cl2 washes of the dilute H2SO4 solution gave a H2O-soluble white solid that proved to be the sulfate salt of the product. This provided, after making the H2O solution basic, extraction with CH2Cl2, and solvent removal, the free base that was converted, as described above, to a second crop of the hydrochloride salt.

DOSAGE: above 12 mg.

DURATION: probably short.

QUALITATIVE COMMENTS: (with 8 mg) I might actually be up to a plus 1, and with a very good feeling. But I cannot say how long it lasted, and it was probably pretty short. It just sort of faded away.

(with 12 mg) At the 25 minute point I am reminded of the experiment, and in another quarter hour I am into something. Will this be another forever threshold? I feel very good, but there is no sparkle.

EXTENSIONS AND COMMENTARY: Here is another example of the presentation of a compound for which there has not yet been an effective level determined. Why? For a very good reason. This is an example of a whole class of compounds that I have called the pseudos, or the gamma-compounds. Pseudo- as a prefix in the literary world generally stands for "false." A pseudopod is a thing that looks like a foot, but isn't one. A pseudonym is a fictitious name. But in chemistry, it has quite a different meaning. If something has a common name, and there is a second form (or isomer, or shape, or orientation) that is possible and it doesn't have a common name, it can be given the name of the first form with a Rpseudo-S attached. Ephedrine is the erythro-isomer of N-methyl-beta-hydroxyamphetamine. There is a second stereoisomer, the threo- isomer, but it has no trivial name. So it is called pseudoephedrine, or the "Sudafed" of sinus decongestant fame.

The pseudo-psychedelics are the 2,4,6-trisubstituted counterparts of the 2,4,5-trisubstituted psychedelics. Almost all of the 2,5-dimethoxy-4-something-or-other compounds are active and interesting whether they be phenethylamines or amphetamines, and it is an exciting fact that the 2,6-dimethoxy-4-something-or-other compounds are going be just as active and just as interesting. A number of examples have already been mentioned. TMA-2 is 2,4,5-trimethoxyamphetamine (a 2,5-dimethoxy-substituted compound with a methoxyl at the 4-position). The pseudo- analogue is TMA-6 (2,4,6-trimethoxyamphetamine) and it is every bit as potent and fascinating. Z-7 could be called pseudo-DOM, and although it is quite a bit down in potency, it is an active drug and will both demand and receive much more clinical study some day.

Will the other 2,4,5-things spawn 2,4,6-things that are active? Without a shadow of a doubt. Chemically, they are much more difficult to synthesize. The 2,5-dimethoxy orientation made the 4-position a natural and easy target. The 2,6-dimethoxy orientation pushes for 3-substitution, and the 4-position is completely unnatural. Tricks are needed, but tricks have now been found. The above synthesis of pseudo-2C-T-4 shows one such trick. This is, in my opinion, the exciting chemistry and psychopharmacology of the next decade. Well over half of all the psychedelic drugs mentioned in Book II are 2,4,5-trisubstituted compounds, and every one of them has a (potentially active) 2,4,6-pseudo-counterpart.

It goes yet further. The antidepressant series of "Ariadne" compounds are 1-phenyl-2-aminobutanes. But the 1-phenyl is again a 2,4,5-trisubstituted compound. The 2,4,6-isomer will give rise to a pseudo-Ariadne family, and I will bet that they too will be antidepressants. The 1-phenyl-2-aminobutane analog of gamma-2C-T-4 is the 2,4,6-analogue and it has been prepared as far as the nitrostyrene. It has not yet been reduced, so it is not yet been evaluated, but it could be a most remarkable psycho-pharmacological probe.

And it goes yet yet further. Think back to the six possible TMA's. TMA and TMA-3 were relatively inactive. And TMA-2 and TMA-6 were the interesting ones. The first gave rise to the last twenty years of psychedelic chemistry, and the other (as speculated upon above) will give rise to the forthcoming ten years. But what of TMA-4 and TMA-5? Both showed activity that was more than TMA but less than that of the -2 or -6 isomers. Could they, some day, provoke yet other families of psychedelics? Maybe the 3-position of these two might be focal points of leverage as to psychological activity. What are the letters that follow y in the Greek alphabet? If I remember correctly, the next letter is the last letter, omega. So, I guess that Nature is trying to tell us something, that the -4 and -5 isomers will not engender interesting families. What a pity. The chemistry is so unthinkably difficult that it would have been a true challenge. My next incarnation, maybe?

Date: 2016-04-22; view: 756