Pihkal

by Alexander Shulgin

  38 2C-SE; 2,5-DIMETHOXY-4-METHYLSELENEOPHENETHYLAMINE

  SYNTHESIS: A suspension of 5.65 g 1,4-dimethoxybenzene in 100 mL

  petroleum ether containing 6.5 mL N,N,NU,NU-tetramethylethylenediamine was magnetically stirred, placed in an inert atmosphere, and cooled to 0 !C with an external ice bath. There was then added 27 mL of 1.6 M

  butyllithium in hexane. The solids present went into solution, and after a few min continued stirring, a fine precipitate appeared. The reaction was allowed to stir while coming up to room temperature.

  There was then added 4.8 g dimethyl diselenide which led to an exothermic reaction, bringing the petroleum ether up to a reflux and showing a color change from white to yellow, to light green, to an eventual brown, all over the course of 30 min. After 2 h additional stirring, the reaction was quenched by pouring into dilute NaOH. The organic phase was separated, and the aqueous phase extracted with 2x75

  mL Et2O. The pooled organics were washed first with dilute NaOH, then with dilute HCl, and then the solvent was removed under vacuum.

  Distillation of the residue at 0.4 mm/Hg gave an early fraction (75-100 !C) that solidified in the receiver and was largely unreacted dimethoxybenzene. A pale yellow oil distilled from 100 to 120 !C

  which proved to be largely 2,5-dimethoxyphenyl methyl selenide.

  Microanalysis gave C = 49.86, 49.69; H = 5.32, 5.47. As C9H12SeO2

  requires C = 46.76, H = 5.23, there is approximately 13%

  dimethoxybenzene present (C8H10O2 requires C = 69.54, H = 7.29). This mixture was used as such, without further purification.

  A mixture of 1.25 g POCl3 and 1.1 g N-methylformanilide was warmed on the steam bath for several min until the color had become a deep claret. There was then added 1.5 g of the 87% pure 2,5-dimethoxyphenyl methyl selenide and the steam bath heating continued for an additional 25 min. The very tarry reaction mixture was poured into 100 mL H2O, producing fine yellow solids almost immediately. These were removed by filtration and distilled at 0.2

  mm/Hg. A first fraction distilling up to 100 !C was a mixture of unreacted ethers and what appeared to be 2,5-dimethoxybenzaldehyde. A second cut distilled at 140-150 !C, solidified to a yellow solid in the receiver, and weighed 1.2 g. A small amount of this product (with mp 91-96 !C) was recrystallized from MeOH to give an analytic sample of 2,5-dimethoxy-4-(methylseleneo)benzaldehyde with a mp 88-92 !C.

  All efforts to achieve a tighter melting range were unsuccessful.

  Anal. (C10H12O3 Se) C,H. Although this benzaldehyde migrates normally on a silica gel TLC plate (Rf of 0.4 employing CH2Cl2 as a solvent) when it is once completely dried on the plate, there seems to be some irreversible reaction with the silica, and the spot will no longer move at all.

  To a solution of 0.85 g 2,5-dimethoxy-4-(methylseleneo)benzaldehyde in 10 mL nitromethane there was added 150 mg anhydrous ammonium acetate, and the solution was heated for 35 min on the steam bath. Removal of the volatiles under vacuum yielded brick-red solids (1.1 g) which were ground under a small amount of MeOH, filtered, and air dried. This yielded 0.88 g of solid 2,5-dimethoxy-4-methylseleneo-'-nitrostyrene with a mp of 170.5-171.5 !C. Recrystallization from IPA or from toluene gave no improvement of mp. Anal. (C11H13NO4Se) C,H.

  A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 0.53 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 0.85 g

  2,5-dimethoxy-4-methylseleneo-'-nitrostyrene in 20 mL hot anhydrous THF. There was an immediate discoloring. After a few minutes further stirring, the temperature was brought up to a gentle reflux on the steam bath for 0.5 h, then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of IPA and, when there was no further activity, the reaction mixture was poured into 500 mL

  dilute H2SO4. This was washed with 2x100 mL CH2Cl2, and then made basic with 5% NaOH. The milky aqueous phase was extracted with 2x100

  mL CH2Cl2, and extensive centrifuging was required to obtain a clear organic phase. Evaporation of the pooled extracts gave 1.6 g of an oil that crystallized. This was distilled at 130-140 !C at 0.15 mm/Hg providing 0.6 g of a white oil that set to a crystalline solid melting at 87-89 !C. This was dissolved in 4 mL boiling IPA, neutralized with 8 drops of concentrated HCl and the formed solids further diluted with IPA with a little anhydrous Et2O. This crystalline product was removed by filtration, washed with Et2O, and air dried to constant weight, yielding 2,5-dimethoxy-4-methylseleneophenethylamine hydrochloride (2C-SE) with a mp of 240-241 !C.

  DOSAGE: perhaps 100 mg.

  DURATION: 6 - 8 h.

  QUALITATIVE COMMENTS: (with 50 mg) My tongue feels as if I had eaten hot food. Overall I got up to a plus 1, and found the effects to be completely benign. I wandered about within the Graves exhibit at the Oakland Museum but there seemed to be only minor enhancement of the visual input.

  (with 70 mg) The water solution of this material has an unspeakable smell. But there is no lasting taste, thank heaven. This is up to a 1.5 + and probably half again would be an effective dose. The first awareness was at 45 minutes, and the plateau lasted from 1.5 hours to about the fourth hour. I was at certain baseline at 8 hours.

  EXTENSIONS AND COMMENTARY: With an entirely new hetero atom in the molecule (the selenium), and with clear indications that large dosages would be needed (100 milligrams. or more), some discretion was felt desirable. There was certainly an odd taste and an odd smell. I remember some early biochemical work where selenium replaced sulfur in some amino acid chemistry, and things got pretty toxic. It might be appropriate to get some general animal toxicity data before exploring those dosages that might get to a +++.

  What doors are opened by the observation that the selenium analog of 2C-T is an active compound? The potency appears to be in the same ball park, whether there is a sulfur atom or a selenium atom there.

  From the point of view of the thing that is hung onto the hetero-atom, the selenium, the most active (and as first approximation the most safe) analogue would be the same ones that are the most potent with sulfur. These would probably be the Se-ethyl, the Se-propyl, or the Se-isopropyl, the analogs of S-ethyl, S-propyl, and S-isopropyl. If one were to be systematic, these would be called 2C-SE-2, 2C-SE-4, and 2C-SE-7. And a very special place might be held for 2C-SE-21, the analogue of 2C-T-21. Not only is this of high potential potency, but it would certainly be the first time that both fluorine and selenium are in the same centrally active drug. In fact, might not this compound, 2C-SE, be the first compound active within the human CNS

  with a selenium atom in it? It is certainly the first psychedelic with this atom in it!

  From the point of view of the hetero-atom itself, there are two more known below selenium in the Periodic Table. Each deserves some special comment. The next atom, directly below selenium, is tellurium. It is more metallic, and its com-pounds have a worse smell yet. I heard a story about a German chemist, many years ago, who was carrying a vial of dibutyl telluride in his pocket in a passenger coach from here to there in Germany, back at about the turn of the century. It fell to the floor and broke. No one could remain in the car, and no amount of decontamination could effectively make the smell tolerable. Scratch one railway coach. But the compound, 2C-TE, would be readily makeable. Dimethyl ditelluride is a known thing.

  However, the atom below tellurium (and at the bottom of that particular column of the Periodic Table) is the element polonium.

  Here one must deal in terms of theory, as far as human activity goes, since there are no non-radioactive isotopes of polonium. The only readily available isotope is that with mass 210, which is also called Radium F, and is an alpha-particle emitter. If this were ever to be put into a living organism, and if it were to seek out and hang around some particular site of action, that area would be thoroughly and completely cooked by alpha-particle emission. It would be a fun academic exercise to make 2C-PO

  (2,5-dimethoxy-4-methylpolo
neophenethylamine), but in no way could it ever go into anyone. I knew an eminent physiologist named Dr. Hardin Jones (now dead) who always argued that the continuing use of drugs would burn out the pleasure center of the brain. It is a certainty that 2C-PO would, quite literally, do this. If I ever made it, I would call it HARDINAMINE in his honor.

  There was an interesting observation associated with the making of 2C-SE. In the synthesis of many of the sulfur compounds (of the 2C-T

  family) is was quite common to find, when there was a quantity of some organic sulfide let go as a by-product of a reaction on a warm summer night, a number of flies coming into the lab to pay a visit. On the first synthesis of the starting material for 2C-SE, a quantity of CH3SeH was let go into the environment. Within minutes, there were two beautiful dragonflies in the lab. A coincidence certainly, but somehow, it was a nice message to receive.

  39 2C-T ; 2,5-DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE

  SYNTHESIS: A solution of 149 g sodium thiosulfate in 300 mL H2O was vigorously stirred. To this there was added, over the course of 10

  min, a solution of 43.2 g benzoquinone in 200 mL acetic acid. After an additional 1 h stirring at room temperature, all volatiles were removed under vacuum. The residual syrup slowly set up as crystals which, after grinding under brine, were removed by filtration and washed with additional brine. These were dissolved in MeOH, clarified by filtration through a Celite bed, and the clear filtrate stripped of solvent under vacuum. The yellow, powdery sodium 2,5-hydroxyphenylthiosulfate weighed 67 g when dry. This intermediate was dissolved in aqueous HCl (50 g in 200 mL H2O containing 400 mL

  concentrated HCl), cooled with an external ice bath, and treated with 250 g zinc dust added at a rate that kept the temperature below 60 !C.

  About 1.5 h were required, and caution must be taken concerning the poisonous hydrogen sulfide that evolves. An additional 50 mL

  concentrated HCl was added, and the aqueous phase decanted from the unreacted zinc metal. This was extracted with 6x100 mL Et2O, and these extracts were pooled, washed with brine, and the solvent removed under vacuum to yield 33.1 g of 2,5-dihydroxythiophenol as pale yellow needles with a mp of 118-119 !C.

  A solution of 118.6 g KOH pellets in 200 mL H2O was placed under N2, and to it was added 24.0 g 2,5-dihydroxythiophenol. With vigorous stirring, there was then added 160 g methyl sulfate at a rate that maintained the temperature at about 60 !C. This took about 2 h.

  After the addition was complete, the mixture was held at reflux for 3

  h, and allowed to stir at ambient temperature overnight. It was then filtered, and the filtrate extracted with 6x100 mL Et2O, the extracts pooled, washed with 2x50 mL brine, dried over anhydrous Na2SO4, and the solvent removed under vacuum. The residue was distilled at 86-88

  !C at 0.04 mm/Hg to provide 25.9 g of 2,5-dimethoxythioanisole as a white oil that crystallized on standing. Its mp was 33-34 !C. An alternate preparation of this compound follows the direct methylation of 2,5-dimethoxythiophenol (see under 2C-T-2 for the preparation of this common intermediate) with methyl iodide.

  To 40 mL dry CH2Cl2 there was added 6.07 g 2,5-dimethoxythioanisole, and this was cooled to 0 !C under N2. To this well stirred solution there was added 13.02 g stannic chloride over the course of 2 min.

  This was followed by the drop-wise addition of dichloromethyl methyl ether over 5 min, and the reaction mixture allowed to stir for an additional 15 min. After returning to room temperature, it was stirred for an additional 1 h. The reaction mixture was poured over 15 g ice, and the organic phase separated, washed with 3x25 mL 3 N

  HCl, with 3x50 mL brine and, after drying over anhydrous Na2SO4, the solvent was removed under vacuum. The residue was a solid and, after recrystallization from MeOH/H2O, gave 5.86 g 2,5-dimethoxy-4-(methylthio)benzaldehyde with a mp of 95-97 !C.

  Purification via the bisulfite complex provided an analytical sample with mp of 99-100 C. Anal. (C10H12O3S) C,H,S. The malononitrile derivative (from equal weights of the aldehyde and malononitrile in EtOH with a drop of triethylamine as catalyst) was recrystallized from an equal volume of EtOH to give orange crystals with a mp of 185-186

  !C. Anal. (C13H12N2O2S) C,H,N,S.

  A solution of 2.1 g 2,5-dimethoxy-4-(methylthio)benzaldehyde in 7.5 mL

  nitromethane was treated with 0.45 g anhydrous ammonium acetate and held at steam bath temperature for 6 h. The deep red solution was stripped of solvent to give a residue that spontaneously crystallized.

  This was ground up under 12 mL MeOH, filtered, and washed with MeOH to yield, after air-drying, 1.7 g of

  2,5-dimethoxy-4-methylthio-'-nitrostyrene as orange solids.

  Recrystallization from EtOH provided rust-orange colored crystals with a mp of 165.5-166 !C. Anal. (C11H13NO4S) C,H,N; S: calcd, 12.56; found, 11.96.

  To a gently refluxing mixture of 1.4 g LAH in 40 mL anhydrous THF

  under an inert atmosphere there was added, dropwise, 1.7 g 2,5-dimethoxy-4-methylthio-'-nitrostyrene in 25 mL THF. The refluxing was continued for 18 h, and the stirring continued for another day at room temperature. There was then added 1.5 mL H2O (diluted with a little THF), 1.5 mL 15% NaOH, and finally 4.5 mL H2O. The white aluminum oxide salts were removed by filtration, and the filter cake washed with THF. The filtrate and washings were combined and stripped of solvent under vacuum yielding a straw-colored residue that crystallized (mp 81-92 !C without purification). This residue was dissolved in 25 mL IPA and neutralized with concentrated HCl. The slightly pink solution spontaneously crystallized. There was added 100 mL anhydrous Et2O, and the white crystalline mass of 2,5-dimethoxy-4-methylthiophenethylamine hydrochloride (2C-T) was removed by filtration, washed with Et2O, and air dried. The final weight was 1.0 g, and had a mp of 232-237 !C. Recrystallization from EtOH provided an analytical sample with mp 240-241 !C. IPA was not a good recrystallization solvent. Anal. (C11H18ClNO2S) C,H,N,S.

  DOSAGE: 60 - 100 mg.

  DURATION: 3 - 5 h.

  QUALITATIVE COMMENTS: (with 60 mg) Poetry was an easy and natural thing. Both the reading of it and the writing of it. This is a potential MDMA substitute since it opens things up but it doesnUt do anything to get in the way.

  (with 75 mg) I am already aware at a quarter of an hour into it! It develops very quickly but very quietly. There are no visuals at all but, rather, a tactile sensitivity, with warm close feelings. This could be very erotic. There is some fantasy to music, but nothing very demanding. The viewing of pictures doesnUt do much either. The drop-off was extremely relaxed, with a good body feeling. At the fifth hour I was able to drift into an excellent, deep sleep with busy dreams. In the morning I felt refreshed and active, without apparent deficit.

  (with 75 mg) I got up to a thin and fragile plus two, but there was a continuing feeling of a hooded cloak brought down over my head.

  Nothing obvious Q it is transparent Q but it somehow separated me from everything around me. I do not think the overall experiment was worth it.

  (with 100 mg) Material all right, but a little bit along the lines of a 'generic' psychedelic effect. Sharper edges than 2C-B. The one true negative, which has been pretty consistent with this drug, is that there is a certain emotional removal. One teeny step removed.

  One is connected with feelings, certainly, but there is a tendency for the intellect to be more evident, in me, than the heart. All this is moderately so. Nothing extreme. Pretty good material, but there are more inter-esting ones. However, if you are looking for a really short one, this is one of the answers. For most people. For me, itUs still around 5 to 6 hours long. I wish we had more shorties, indeed.

  (with 125 mg) There was some physical tummy uncertainty, but once that was past, talking was extremely easy. This is probably really psychedelic, but I am not really sure why, as there is not much in the way of visuals. Dropping was noted just after hour number three, and I was at baseline three hours later.

  EXTENSIONS AND COMMENTARY: The earliest work with the sulfur atom was with the three-carbon chain materials
, the ALEPHs. It was only after a considerable time of working with them, and trying to come to peace with their property of being so different from person to person as to potency, that the two-carbon homologues were looked at. Although the first of these (this compound, called 2C-T) was prepared at the same time as ALEPH-1, there was a lapse of about four years between their trials. The relatively low potency of 2C-T was a bit discouraging.

  But the methodical pursuit of the higher 2C-T's (to parallel the higher ALEPHs) proved to be a treasure house, and they have been explored much further than any of the ALEPHs.

  A note on the RTS in 2C-T. Many, in fact most, of the 2C's have their name based on the last letter of the amphetamine prototype. 2C-B from DOB, 2C-C from DOC, 2C-I from DOI, 2C-N from DON, etc. And since the original name for ALEPH-1 was DOT (the desoxy- and a thiomethyl group at the 4-position), the 2C-T naming followed this general pattern.

  And as a note on the subsequent numbering, they (both the ALEPHs and the 2C-TUs) are assigned numbers as they are thought up. There is no structural significance in the number but they have been, like the houses on the streets in residential Tokyo, assigned numbers in strict historical order, documenting the sequence of construction rather than the relative position down the side of the street.

  Both of the homologous mono-ethoxy Tweetios of 2C-T have been synthesized and evaluated. The 2-EtO-homologue of 2C-T is 2-ethoxy-5-methoxy-4-methylthiophenethylamine, or 2CT-2ETO. The benzaldehyde (2-ethoxy-5-methoxy-4-(methylthio)benzaldehyde) was an oil, the nitrostyrene intermediate had a melting point of 137-138 !C, and the final hydrochloride a melting point of 215-216 !C. The effects were felt very quickly, and there was a blurring of vision.

  However, the highest dose tried, 50 milligrams, was not able to produce a greater-than-plus one state, and what did occur, lasted for only 4 hours.

  The 5-EtO-homologue of 2C-T is