Pihkal

by Alexander Shulgin

  The 2,5-DiEtO- homologue of 2C-B is

  4-bromo-2,5-diethoxyphenethylamine, or 2CB-2,5-DIETO. The unbrominated impure benzaldehyde (2,5-diethoxybenzaldehyde) had a melting point of about 57 !C, the unbrominated impure nitrostyrene intermediate a melting point of about 60 !C, and the final hydrochloride a melting point of 230-231 !C. The hydrobromide salt had a melting point of 192-193 !C. At levels of 55 milligrams, there was only a restless sleep, and strange dreams. The active level is not yet known.

  I have been told of some studies that have involved a positional rearrangement analogue of 2C-B. This is 2-bromo-4,5-dimethoxyphenethylamine (or 6-BR-DMPEA). This would be the product of the elemental bromination of DMPEA, and it has been assayed as the hydrobromide salt. Apparently, the intravenous injection of 60 milligrams gave a rapid rush, with intense visual effects reported, largely yellow and black. Orally, there may be some activity at the 400 to 500 milligram area, but the reports described mainly sleep disturbance. This would suggest a stimulant component.

  The N-methyl homologue of this rearranged compound was even less active.

  21 3C-BZ; 4-BENZYLOXY-3,5-DIMETHOXYAMPHETAMINE

  SYNTHESIS: A solution of 268 g 2,6-dimethoxyphenol and 212 g allyl bromide in 700 mL dry acetone was treated with 315 g anhydrous K2CO3

  and held at reflux for 16 h. The solvent was removed under vacuum, and the residue dissolved in H2O and extracted with 3x100 mL CH2Cl2.

  The pooled extracts were washed with 5% NaOH, then with H2O, and the solvent removed under vacuum. The residue, which weighed 245 g, was stirred and heated in an oil bath to 230 !C at which point an exothermic reaction set in. The heating was maintained at 230 !C for 0.5 h, and then the reaction mixture distilled. There was obtained a total of 127 g of 5-allyl-1,3-dimethoxy-2-hydroxybenzene as a colorless distillate, that was identical in all respects to natural 5-methoxyeugenol obtained from Oil of Nutmeg.

  A solution containing 40.4 g 5-methoxyeugenol and 26.6 g benzyl chloride in 65 mL EtOH was added, all at once, to a hot and well stirred solution of 11.7 g KOH in 500 mL EtOH. The potassium salt of the phenol crystallized out immediately. By maintaining reflux conditions, this slowly redissolved, and was replaced by the steady deposition of KCl. After 6 h, the reaction mixture was cooled, and the solids removed by filtration. The filtrate was stripped of solvent under vacuum to give 57 g of crude 5-allyl-2-benzyloxy-1,3-dimethoxybenzene. This was dissolved in a solution of 60 g KOH in 80 mL EtOH and heated on the steam bath for 16

  h. The reaction mixture was quenched in 500 mL H2O, and extracted with 2x200 mL CH2Cl2. Removal of the solvent under vacuum gave 35.6 g of crude 2-benzyloxy-1,3-dimethoxy-5-propenylbenzene.

  To a stirred, ice-cold solution of 33.6 g of the above impure 2-benzyloxy-1,3-dimethoxy-5-propenylbenzene and 13.6 g pyridine in 142

  mL acetone, there was added 24.6 g tetranitromethane. After stirring for 3 min, there was added a solution of 7.9 g KOH in 132 mL H2O, followed by additional H2O. The oily phase that remained was H2O

  washed, and then diluted with an equal volume of MeOH. This slowly set up to yellow crystals, which were removed by filtration and washed sparingly with MeOH. There was obtained 9.2 g 1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-nitropropene with a mp of 84-85

  !C. An analytical sample, from EtOH, had a mp of 86-87 !C.

  To a refluxing suspension of 5.5 g LAH in 360 mL anhydrous Et2O under an inert atmosphere, there was added 8.6 g 1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-nitropropene by letting the condensing Et2O leach out a saturated solution from a modified Soxhlet condenser. The addition took 1.5 h and the refluxing was maintained for an additional 4 h. After cooling, the excess hydride was destroyed by the cautious addition of 330 mL of 1.5 N H2SO4. The aqueous phase was heated up to 80 !C, filtered through paper to remove a small amount of insoluble material, and treated with a solution of 8

  g picric acid in 150 mL boiling EtOH. Cooling in the ice chest overnight gave globs of the amine picrate, but no clear signs of crystallization. These were washed with cold H2O, then dissolved in 5% NaOH to give a bright yellow solution. This was extracted with 3x150 mL CH2Cl2, the solvent removed under vacuum, the residue dissolved in 300 mL anhydrous Et2O, freed from a little particulate material by filtration through paper, and then saturated with hydrogen chloride gas. There was thus obtained, after filtering, Et2O washing and air drying, 2.5 g 4-benzyloxy-3,5-dimethoxyamphetamine hydrochloride (3C-BZ) as a white solid with a mp of 161-164 !C.

  DOSAGE: 25 - 200 mg.

  DURATION: 18 - 24 h.

  QUANTITATIVE COMMENTS: (with 25 mg) I went into an emotionally brittle place, and for a while I was uncomfortable with childhood reminiscences. The seeing of my family's Christmas tree in my mind was almost too much. I cried.

  (with 50 mg) The action is distinct Q wakeful Q alerting and wound up. Hypnogogic imagery, and I could not sleep at night with my mind doing many uncontrolled, tangential, busy things. I had fleeting nausea early in the process.

  (with 100 mg) I took this in two portions. Following 50 milligrams I was aware of a slight light-headedness at a half-hour, but there was little else. At 1 1/2 hours, I took the second 50 milligrams and the augmentation of effects was noted in another half hour. The experience quietly built up to about the fifth hour, with some erotic fantasy and suggestions of changes in the visual field. I could not sleep until the twelfth hour, and my dreams were wild and not too friendly. There was no body threat from this, but I was not completely baseline until the next day. I am not too keen to do this again Q it lasts too long.

  (with 100 mg) No effects.

  (with 150 mg) This is in every way identical to 100 micrograms of LSD.

  (with 180 mg) I can compare this directly to TMA which was the material I took last week. Many similarities, but this is unquestionably more intense than the TMA was at 200 milligrams. It is hard to separate the degree of impact that this drug has, from the simple fact that it lasts forever, and I was getting physically tired but I couldnUt sleep. There is some amphetamine-like component, more than with TMA.

  EXTENSIONS AND COMMENTARY: Two points are worthy of commentary; the potency and the promise of 3C-BZ.

  As to potency, there is such uncertainty as to the effective dose, that it is for all intents and purposes impossible to predict just what dose should be considered for a person's first time with this.

  The choice of quotations was made with the intention of giving a picture of this scatter. A total of ten subjects have explored this compound, and the very broad range given above, 25 to 200 milligrams, reflects the degree of variation that has been encountered.

  Which is a shame, because the concept of a new ring such as is found here on the 4-position would have allowed an extremely wide array of substituents. Electron-rich things, electron-poor things, heavy things, light things, and on and on. This could have been a location of much variation, but it is a possibility that the uncertainties of dosage might extrapolate to these novel ring substitutions as well.

  Only a single variation was made, the 4-fluorobenzyl analogue. This was prepared following exactly the procedure given here for 3C-BZ, except for the replacement of benzyl chloride with 4-fluorobenzyl chloride. The allyl intermediate was an oil, but the propenyl isomer gave solids with a melting point of 59-60 !C from hexane. The nitrostyrene was a yellow crystalline solid from methanol with a melting point of 98-99 !C. The end product, 3,5-dimethoxy-4-(4-fluorobenzyloxy)amphetamine hydrochloride (3C-FBZ) was a white solid with a melting point of 149-150 !C. It has been assayed only up to 4 milligrams and there was absolutely no activity of any kind observed at that level.

  22 2C-C; 2,5-DIMETHOXY-4-CHLOROPHENETHYLAMINE

  SYNTHESIS: (from 2C-H) The free base of 2,5-dimethoxyphenethylamine was generated from its salt (see recipe for 2C-H for the preparation of this compound) by treating a solution of 16.2 g of the hydrochloride salt in 300 mL H2O with aqueous NaOH, extraction with 3x75 mL CH2Cl2, and removal of the solvent from the pooled extracts under vacuum. The colorless residue was dis
solved in 75 mL glacial acetic acid (the solids that initially formed redissolved completely) and this was cooled to 0 !C with an external ice bath. With vigorous stirring, there was added 4.0 mL of liquid chlorine, a little bit at a time with a Pasteur pipette. The theoretical volume was 3.4 mL, but some was lost in pipetting, some on contact with the 0 !C acetic acid, and some was lost by chlorination of the acetic acid. The reaction turned a dark amber color, was allowed to stir for an additional 10

  min, then quenched with 400 mL H2O. This was washed with 3x100 mL

  CH2Cl2 (which removed some of the color) then brought to neutrality with dilute aqueous NaOH and treated with a small amount of sodium dithionite which discharged most of the color (from deep brown to pale yellow). The reaction was made strongly basic with aqueous KOH, and extracted with 3x75 mL CH2Cl2. The pooled extracts were washed once with H2O and the solvent was removed under vacuum leaving about 10 mL

  of a deep amber oil as residue. This was dissolved in 75 mL IPA and neutralized with concentrated HCl which allowed spontaneous crystallization. These crystals were removed by filtration, washed with an additional 20 mL IPA, and air-dried to constant weight. There was thus obtained 4.2 g 2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) with a mp of 218-221 !C. Recrystallization from IPA increased this to 220-222 !C. The position of chlorination on the aromatic ring was verified by the presence of two para-protons in the NMR, at 7.12 and 7.20 ppm from external TMS, in a D2O solution of the hydrochloride salt.

  Synthesis from 2C-B. To a solution of 7.24 g 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 4.5 g phthalic anhydride in 100 mL anhydrous DMF there was added molecular sieves.

  After 16 h reflux, the reaction mixture was cooled and the sieves removed by filtration. The addition of a little CH2Cl2 prompted the deposition of yellow crystals which were recrystallized from EtOH.

  The resulting 1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane weighed 7.57 g and had a mp of 141-142 !C. Anal. (C18H16BrNO4) C,H,N,Br.

  A solution of 14.94 g of

  1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane and 4.5 g cuprous chloride in 300 mL anhydrous DMF was heated for 5 h at reflux.

  The cooled mixture was poured into 20 mL H2O that contained 13 g hydrated ferric chloride and 3 mL concentrated HCl. The mixture was maintained at about 70 !C for 20 min, and then extracted with CH2Cl2.

  After washing the pooled organic extracts with dilute HCl and drying with anhydrous MgSO4, the volatiles were removed under vacuum to provide a solid residue. This was recrystallized from EtOH to provide 12.18 g of 1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane as yellow needles that had a mp of 138-140 !C. Anal. (C18H16ClNO4) C,H,N,Cl.

  To 60 mL absolute EtOH there was added 12.2 g 1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane and 2.9 mL of 100% hydrazine. The solution was held at reflux for 15 min. After cooling, the cyclic hydrazone by-product was removed by filtration, and the alcoholic mother liquors taken to dryness under vacuum. The residue was distilled at 145-155 !C at 0.05 mm/Hg to give 5.16 g of a clear, colorless oil. This was dissolved in anhydrous Et2O and treated with hydrogen chloride gas, producing 2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) as white crystals with a mp of 220-221 !C. Anal. (C10H15Cl2NO2) C,H,N.

  DOSAGE: 20 - 40 mg.

  DURATION: 4 - 8 h.

  QUALITATIVE COMMENTS: (with 20 mg) This is longer lived than 2C-B, and there is a longer latency in coming on. It took an hour and a half, or even two hours to get there. It had a slight metallic overtone.

  (with 24 mg) I was at a moderately high and thoroughly favorable place, for several hours. It seemed to be a very sensual place, but without too much in the way of visual distraction.

  (with 40 mg) There were a lot of visuals Q something that I had noted at lower levels. There seems to be less stimulation than with 2C-B, and in some ways it is actually sedating. And yet I was up all night.

  It was like a very intense form of relaxation.

  EXTENSIONS AND COMMENTARY: Other reports mention usage of up to 50

  milligrams which seems to increase yet further the intensity and the duration. I have one report of an intravenous administration of 20

  milligrams, and the response was described as overwhelming. The effects peaked at about 5 minutes and lasted for perhaps 15 minutes.

  The halogens represent a small group of atoms that are unique for a couple of reasons. They are all located in a single column of the periodic table, being monovalent and negative. That means that they can be reasonably stable things when attached to an aromatic nucleus.

  But, being monovalent, they cannot be modified or extended in any way.

  Thus, they are kind of a dead end, at least as far as the 2C-X series is considered. The heaviest, iodine, was explored as the phen-ethylamine, as 2C-I, and as the amphetamine as DOI. These are the most potent. The next lighter is bromine, where the phenethylamine is 2C-B and the amphetamine is DOB. These two are a bit less potent, and are by far the most broadly explored of all the halides. Here, in the above recipe, we have the chlorine counterpart, 2C-C. There is also the corresponding amphetamine DOC. These are less potent still, and much less explored. Why? Perhaps because chlorine is a gas and troublesome to handle (bromine is a liquid, and iodine is a solid). The fluorine analogue is yet harder to make, and requires procedures that are indirect, because fluorine (the lightest of all the halides) is not only a gas, but is dangerous to handle and does not react in the usual halogen way. There will be mention made of 2C-F, but DOF is still unexplored.

  The treatment of the 2C-B phthalimide described above, with cuprous cyanide rather than cuprous chloride, gave rise to the cyano analog which, on hydrolysis with hydrazine, yielded 2,5-dimethoxy-4-cyanophenethylamine (2C-CN). Hydrolysis of this with hot, strong base gave the corresponding acid, 2,5-dimethoxy-4-carboxyphenethylamine, 2C-COOH. No evaluation of either of these compounds has been made in the human animal, as far as I know.

  23 2C-D; LE-25; 2,5-DIMETHOXY-4-METHYLPHENETHYLAMINE

  SYNTHESIS: Into 1 L H2O that was being stirred magnetically, there was added, in sequence, 62 g toluhydroquinone, 160 mL 25% NaOH, and 126 g dimethyl sulfate. After about 2 h, the reaction mixture was no longer basic, and another 40 mL of the 25% NaOH was added. Even with stirring for a few additional days, the reaction mixture remained basic. It was quenched in 2.5 L H2O, extracted with 3x100 mL CH2Cl2

  and the pooled extracts stripped of solvent under vacuum. The remaining 56.4 g of amber oil was distilled at about 70 !C at 0.5

  mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid. The aqueous residues, on acidification, provided a phenolic fraction that distilled at 75-100 !C at 0.4 mm/Hg to give 5.8 g of a pale yellow distillate that partially crystallized. These solids (with mp of 54-62 !C) were removed by filtration, and yielded 3.1 g of a solid which was recrystallized from 50 mL hexane containing 5 mL toluene.

  This gave 2.53 g of a white crystalline product with a mp of 66-68 !C.

  A second recrystallization (from hexane) raised this mp to 71-72 !C.

  The literature value given for the mp of 2-methyl-4-methoxyphenol is 70-71 !C. The literature value given for the mp of the isomeric 3-methyl-4-methoxyphenol is 44-46 !C. This phenol, on ethylation, gives 2-ethoxy-5-methoxytoluene, which leads directly to the 2-carbon 2CD-5ETO (one of the Tweetios) and the 3-carbon Classic Lady IRIS.

  A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide was heated for 10 min on the steam bath, and then there was added 30.4 g of 2,5-dimethoxytoluene. Heating was continued for 2.5 h, and the viscous, black, ugly mess was poured into 600 mL of warm H2O and stirred overnight. The resulting rubbery miniature-rabbit-droppings product was removed by filtration and sucked as free of H2O as possible. The 37.2 g of wet product was extracted on the steam-bath with 4x100 mL portions of boiling hexane which, after decantation and cooling, yielded a total of 15.3 g of yellow crystalline product.

  This, upon recrystallization from 150 mL boiling hexane, gave pale yell
ow crystals which, when air dried to constant weight, represented 8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde, and had a mp of 83-84 !C.

  Anal. (C8H12O3) C,H,N. The Gattermann aldehyde synthesis gave a better yield (60% of theory) but required the use of hydrogen cyanide gas. The malononitrile derivative, from 5.7 g of the aldehyde and 2.3

  g malononitrile in absolute EtOH, treated with a drop of triethylamine, was an orange crystalline product. A sample recrystallized from EtOH gave a mp of 138.5-139 !C.

  A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde in 30 g nitromethane was treated with 1.1 g anhydrous ammonium acetate and heated for 50 min on the steam bath. Stripping off the excess nitromethane under vacuum yielded orange crystals which weighed 12.2

  g. These were recrystallized from 100 mL IPA providing yellow crystals of 2,5-dimethoxy-4-methyl-'-nitrostyrene which weighed, when dry, 7.70 g. The mp was 117-118 !C, and this was increased to 118-119

  !C upon recrystallization from benzene/heptane 1:2.

  To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under an inert atmosphere, there was added 7.7 g 2,5-dimethoxy-4-methyl-'-nitrostyrene in 35 mL THF over the course of 0.5 h. This reaction mixture was held at reflux for 24 h, cooled to room temperature, and the excess hydride destroyed with 25 mL IPA.

  There was then added 7 mL 15% NaOH, followed by 21 mL H2O. The granular gray mass was filtered, and the filter cake washed with 2x50

  mL THF. The combined filtrate and washes were stripped of their volatiles under vacuum to give a residue weighing 7.7 g which was distilled at 90-115 !C at 0.3 mm/Hg to provide 4.90 g of a clear, white oil, which crystallized in the receiver. This was dissolved in 25 mL IPA, and neutralized with concentrated HCl which produced immediate crystals of the salt. These were dispersed with 80 mL