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by Alexander Shulgin


  There is the 3-hydrogen atom which can become a 3-methyl group to produce a compound called GANESHA. This is a fine elephant-headed Indian God who is the symbol of worldly wisdom and also has been seen as the creator of obstacles. Here I really blew it; the Classic Lady turned out to be a Classic Gentle-man; not even the name is feminine.

  There is the 4-methyl group which can become a 4-ethyl group to produce a compound called HECATE who presided over magic arts and spells. There is the 5-methoxy group which can become a 5-ethoxy group to produce a compound called IRIS, who is the Goddess of the rainbow. And there is the 6-hydrogen atom which can become a 6-methyl group to produce a compound called JUNO, who is pretty much a ladyUs lady, or should I say a woman's woman.

  GANESHA, 2,5-dimethoxy-3,4-dimethylamphetamine has been made, and has proven to be an extraordinary starting point for a large series of potent phenethylamines and amphetamines which are described in this book. HECATE was given a synonym early in this process, and is now known as DOET (2,5-dimethoxy-4-ethylamphetamine). IRIS has also been entered under her name, and the other ethoxy homologue, FLORENCE, would be easily made based on the preparation of the phenethylamine analogue, 2CD-2ETO. Perhaps it has already been made somehow, somewhere, as I have noted that I have claimed its citrate salt as a new compound in a British patent. And, finally, JUNO

  (3,6-dimethoxy-2,4-dimethylamphetamine) has been made (from 2,5-dimethoxy-m-xylene, which was reacted with POCl3 and N-methylformanilide to the benzaldehyde, mp 53-54 !C, and to the nitrostyrene with nitroethane, mp 73-74 !C from cyclohexane, and to the final amine hydrochloride with LAH in THF). Rather amazingly, I have had JUNO on the shelf for almost 14 years and have not yet gotten around to tasting it.

  9 ASB; ASYMBESCALINE; 3,4-DIETHOXY-5-METHOXYPHENETHYLAMINE

  SYNTHESIS: To a solution of 32 g of 5-bromobourbonal in 150 mL DMF

  there was added 31 g ethyl iodide and 32 g of finely ground 85% KOH

  pellets. There was the formation of a purple color and a heavy precipitate. On gradual heating to reflux, the color faded to a pale yellow and the precipitate dissolved over the course of 1 h. The heating was continued for an additional 1 h. The reaction mixture was added to 1 L H2O, and extracted with 2x150 mL of petroleum ether. The extracts were pooled, washed with 2x200 mL 5% NaOH and finally with H2O. After drying over anhydrous K2CO3 the solvents were removed under vacuum to yield 36 g of crude 3-bromo-4,5-diethoxybenzaldehyde as an amber liquid. This was used without purification for the following step. Distillation at 105-115 !C at 0.3 mm/Hg provided a white sample which did not crystallize. Anal. (C11H13BrO3 ) C,H.

  A mixture of 36 g 3-bromo-4,5-diethoxybenzaldehyde and 17 mL

  cyclohexylamine was heated with an open flame until it appeared to be free of H2O. The residue was put under a vacuum (0.4 mm/Hg) and distilled at 135-145 !C, yielding 42 g 3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine as a viscous light greenish oil. This slowly set to a crystalline glass with a mp of 60-61 !C. Recrystallization from hexane gave a white crystalline product without any improvement in the mp. Anal. (C17H24BrNO2) C,H.

  This is a chemical intermediate to a number of active bases, taking advantage of the available bromine atom. This can be exchanged with a sulfur atom (leading to 5-TASB and 3-T-TRIS) or with an oxygen atom as described below.

  A solution of 18 g 3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine in 250 mL anhydrous Et2O was placed in an atmosphere of He, stirred magnetically, and cooled with an external dry ice/acetone bath. Then 36 mL of a 1.5 M solution of butyllithium in hexane was added over 2

  min, producing a clear yellow solution. This was stirred for 10 min.

  There was then added 30 mL of butyl borate at one time, the stirring continued for 5 min. The stirred solution was allowed to return to room temperature. There was added 150 mL of saturated aqueous ammonium sulfate. The Et2O layer was separated, and the aqueous phase extracted with another 75 mL Et2O. The combined organic phases were evaporated under vacuum. The residue was dissolved in 100 mL MeOH, diluted with 20 mL H2O, and then treated with 15 mL 35% H2O2 added over the course of 2 min. This mildly exothermic reaction was allowed to stir for 15 min, then added to 500 mL H2O. This was extracted with 2x100 mL CH2Cl2 and the solvent removed under vacuum. The residue was suspended in 150 mL dilute HCl and heated on the steam bath for 0.5 h.

  Stirring was continued until the reaction was again at room temperature, then it was extracted with 2x75 mL CH2Cl2. These extracts were pooled and extracted with 3x100 mL dilute aqueous KOH.

  The aqueous extracts were washed with CH2Cl2, reacidified with HCl, and reextracted with 2x75 mL CH2Cl2. These extracts were pooled, and the solvent removed under vacuum to yield a brown residue. This was distilled at 107-127 !C at 0.4 mm/Hg to yield 8.3 g of 3,4-diethoxy-5-hydroxybenzaldehyde as an oil that set to a tan solid.

  Recrystallization from cyclohexane gave a white product with a mp of 70.5-71.5 !C. Anal. (C11H14O4) C,H.

  A solution of 8.3 g of 3,4-diethoxy-5-hydroxybenzaldehyde and 3.0 g KOH in 75 mL EtOH was treated with 5 mL methyl iodide and stirred at room temperature for 5 days. The reaction mixture was added to 400 mL

  H2O and extracted with 2x50 mL CH2Cl2. The extracts were pooled, washed with 2x150 mL dilute NaOH, and the solvent removed under vacuum. The residual oil was distilled at 95-110 !C at 0.3 mm/Hg to yield 8.2 g of 3,4-diethoxy-5-methoxybenzaldehyde as a pale yellow liquid. This product was a crystalline solid below 20 !C but melted upon coming to room temperature. It was analyzed, and used in further reactions as an oil. Anal. (C12H16O4) C,H.

  To a solution of 6.4 g 3,4-diethoxy-5-methoxybenzaldehyde in 40 mL

  nitromethane there was added about 0.5 g anhydrous ammonium acetate, and this was held at reflux for 1 h. The excess solvent/reagent was removed under vacuum, producing a red oil which set up to crystals.

  These were recrystallized from 40 mL boiling MeOH to yield 3.0 g of 3,4-diethoxy-5-methoxy-'-nitrostyrene as yellow plates, with a mp of 89-90 !C. Anal. (C13H17NO5) C,H.

  A solution of 3.0 g LAH in 150 mL anhydrous THF under He was cooled to 0 !C and vigorously stirred. There was added, dropwise, 2.1 mL of 100% H2SO4, followed by the dropwise addition of a solution of 3.5 g 3,4-diethoxy-5-methoxy-'-nitrostyrene in 30 mL anhydrous THF, over the course of 10 min. The addition was exothermic. The mixture was held at reflux on the steam bath for 30 min. After cooling again, the excess hydride was destroyed with IPA, followed by the addition of 10%

  NaOH sufficient to covert the aluminum oxide to a white, granular form. This was removed by filtration, the filter cake washed with IPA, the mother liquor and filtrates combined, and the solvents removed under vacuum to provide a yellow oil. This residue was added to 100 mL dilute H2SO4 producing a cloudy suspension and some yellow insoluble gum. This was washed with 2x75 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 2x75 mL CH2Cl2.

  The solvent was removed from these pooled extracts and the residue distilled at 110-135 !C at 0.4 mm/Hg to provide 2.0 g of a colorless liquid. This was dissolved in 7 mL IPA, neutralized with about 40

  drops of concentrated HCl, followed by 50 mL anhydrous Et2O with stirring. The initially clear solution spontaneously deposited a white crystalline solid. This was diluted with an additional 30 mL

  Et2O, let stand for 1 h, and the solids removed by filtration. After Et2O washing, the product was air-dried to yield 1.25 g of 3,4-diethoxy-5-methoxyphenethylamine hydrochloride (ASB) with a mp of 142-143 !C. Anal. (C13H22ClNO3) C,H.

  DOSAGE: 200 - 280 mg.

  DURATION: 10 - 15 h.

  QUALITATIVE COMMENTS: (with 240 mg) There was a pleasant and easy flow of day-dreaming thoughts, quite friendly and somewhat erotic.

  There was a gentle down-drift to my starting baseline mental status by about midnight (I started at 9:00 AM). I never quite made it to a +++, and rather regretted it.

  (with 280 mg) The plateau of effect was evident by hour two, but I found the experience lacking the visual and interpretive richness that I had
hoped for. Sleep was very fitful after the effects had largely dropped Q it was hard to simply lie back and relax my guard Q and even while being up and about the next day I felt a residual plus one.

  Over all, there were few if any of the open interactions of 2C-B or LSD. Some negative side seemed to be present.

  (with 280 mg) The entire session was, in a sort of way, like being in a corridor outside the lighted halls where a beautiful mescaline experience is taking place, sensing the light from behind a grey door, and not being able to find my way in from the dusky underside passageways. This is sort of a gentle sister of mescaline, but with a tendency to emphasize (for me, at this time) the negative, the sad, the struggling. Sleep was impossible before the fifteenth hour. When I tried, I got visions of moonlight in the desert, with figures around me which were the vampire-werewolf aspect of the soul, green colored and evil. I had to sit quietly in the living room and wait patiently until they settled back to wherever they belonged and stopped trying to take over the scene. During the peak of the experience, my pulse was thready, somewhat slowed, and uneven. There was a faint feeling of physical weirdness.

  EXTENSIONS AND COMMENTARY: This specific amine was a target for a single study in cats many years ago, in Holland, using material obtained from Hoffman La Roche in Basel. Their findings are hard to evaluate, in that 200 milligrams was injected into a 3.75 kilogram cat (53 mg/Kg), or about twice the dosage that they used in their studies with metaescaline. Within 5 minutes there were indications of catatonia, and within a half hour the animal was unable to walk. This condition persisted for two days, at which time the animal died.

  Although this dose was many times that used in man, perhaps hints of the physical unease and long action are there to be gleaned. The consensus from over a half dozen experiments is that there is not enough value to be had to offset the body load experienced.

  A comment is needed on the strange name asymbescaline! In the marvelous world of chemical nomenclature, bi- (or di-) usually means two of something, and tri- and tetra- quite reasonably mean three and four of something. But occasionally there can be an ambiguity with bi (or tri or tetra) in that bi some-thing-or-other might be two something-or-others hooked together or it might be two things hooked onto a something-or-other. So, the former is called bi- and the latter is called bis-. This compound is not two escalines hooked together (bi-escaline) but is only one of them with two ethyl groups attached (bis-escaline or bescaline). And since there are two ways that this can be done (either symmetrically or asymmetrically) the symmetric one is called symbescaline (or SB for short) and this one is called asymbescaline (or ASB for short). To complete the terminology lecture, the term tri- becomes tris- (the name given for the drug with all three ethoxy groups present in place of the methoxys of mescaline) and the term tetra- mutates into the rather incredible tetrakis-!

  10 B; BUSCALINE; 4-(n)-BUTOXY-3,5-DIMETHOXYPHENETHYLAMINE

  SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for preparation), 100 mg decyltriethylammonium iodide, and 11 g n-butyl bromide in 50 mL anhydrous acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and held at reflux for 10 h. An additional 6

  g of n-butyl bromide was added to the mixture, and the refluxing continued for another 48 h. The mixture was filtered, the solids washed with acetone, and the solvent from the combined filtrate and washes removed under vacuum. The residue was suspended in acidified H2O, and extracted with 3x175 mL CH2Cl2. The pooled extracts were washed with 2x50 mL 5% NaOH, once with dilute HCl, and then stripped of solvent under vacuum giving 13.2 g of a deep yellow oil. This was distilled at 132-145 !C at 0.2 mm/Hg to yield 5.0 g of 4-(n)-butyloxy-3,5-dimethoxyphenylacetonitrile as a pale yellow oil which set up to crystals spontaneously. The mp was 42-43 !C. Anal.

  (C14H19NO3) C H N.

  A solution of AH was prepared by the cautious addition of 0.67 mL of 100% H2SO4 to 25 mL of 1.0 M LAH in THF, which was being vigorously stirred under He at ice bath temperature. A total of 4.9 g of 4-(n)-butyloxy-3,5-dimethoxyphenylacetonitrile was added as a solid over the course of 10 min. Stirring was continued for another 5 min, then the reaction mixture was brought to reflux on the steam bath for another 45 min. After cooling again to room temperature, IPA was added to destroy the excess hydride (about 5 mL) followed by 10 mL of 15% NaOH which was sufficient to make the aluminum salts loose, white, and filterable. The reaction mixture was filtered, the filter cake washed with IPA, and the mother liquor and washes combined and the solvent removed under vacuum to yield an amber oil. This residue was treated with dilute H2SO4 which generated copious solids. Heating this suspension effected solution, and after cooling, all was washed with 3x50 mL CH2Cl2. The aqueous phase was made basic with aqueous NaOH, and the product extracted with 2x100 mL CH2Cl2. The extracts were evaporated to a residue under vacuum, and this was distilled at 128-138 !C at 0.5 mm/Hg yielding 3.8 g of a colorless oil. This was dissolved in 40 mL IPA, neutralized with concentrated HCl (about 55

  drops required) and, with vigorous stirring, 80 mL of anhydrous Et2O

  was added which produced fine white plates. After standing for several h, the product was filtered, washed with 20% IPA in Et2O, and finally with Et2O. Air drying yielded 3.9 g of 4-(n)-butyloxy-3,5-dimethoxyphenethylamine hydrochloride (B) with a mp of 152-153 !C. An analytical sample melted at 155-157 !C. Anal.

  (C14H24ClNO3) C,H,N.

  DOSAGE: greater than 150 mg.

  DURATION: several hours.

  QUALITATIVE COMMENTS: (with 120 mg) There is a strange taste, not really bitter, it does not linger. The slight change of baseline has certainly disappeared by the eighth hour. No noticeable changes in either the visual or the auditory area.

  (with 150 mg) Throughout the experiment it was my impression that whatever effects were being felt, they were more in body than mind.

  The body load never mellowed out, as it would have with mescaline, after the first hour or two. Mental effects didnUt develop in any interesting way. I was aware of brief heart arrhythmia. Tummy was uncomfortable, off and on, and there was light diarrhea. Even as late as the fifth hour, my feet were cold, and the whole thing left me with a slightly uncomfortable, 'Why did I bother?' feeling.

  EXTENSIONS AND COMMENTARY: There is a jingle heard occasionally in chemical circles, concerning the homologues of methyl. It goes, RThere's ethyl and propyl, but butyl is futile.S And to a large measure this is true with the 4-position homologues of mescaline.

  This butyl compound, B or Buscaline, had originally been patented in England in 1930 without any physical or pharmacological description, and the few physical studies that had involved it (lipophilic this and serotonin that) suggested that it was less active than mescaline.

  In principle, the 5-, the 6-, the 7- and the on-up homologues might be called amylescaline (possibly pentescaline?), hexescaline, heptescaline (possibly septescaline), and God-knows-what-scaline.

  They would certainly be easily makeable, but there would be little value that could be anticipated from nibbling them. In keeping with the name B (for butoxy), these would be known as A (for amyloxy, as the use of a P could confuse pentoxy with propoxy), as H (for hexyloxy, but careful; this letter has been used occasionally for DMPEA, which is Homopiperonylamine), and as S (the H for heptyloxy has been consumed by the hexyloxy, so let's shift from the Greek hepta to the Latin septum for the number seven). It seems most likely that the toxic symptoms that might well come along with these phenethylamines would discourage the use of the dosage needed to affect the higher centers of the brain. The same generally negative feeling applies to the amphetamine counterparts 3C-B, 3C-A, 3C-H and 3C-S.

  A brief reiteration of the 2C-3C nomenclature, to avoid a possible misunderstanding. The drug 2C-B is so named in that it is the two-carbon chain analogue of the three-carbon chain compound DOB. The drug 3C-B is so named because it is the three-carbon chain analogue of the two-carbon chain compound Buscaline, or more simply, B. There is no logical connection whatsoever, either structural or p
harmacological, between 2C-B and 3C-B.

  11 BEATRICE; N-METHYL-DOM; 2,5-DIMETHOXY-4,N-DIMETHYLAMPHETAMINE

  SYNTHESIS: A fused sample of 5.0 g of white, crystalline free base 2,5-dimethoxy-4-methylamphetamine, DOM, was treated with 10 mL ethyl formate, and held at reflux on the steam bath for several h. Removal of the solvent gave 5.5 g of a white solid, which could be recrystallized from 15 mL MeOH to give 3.8 g of fine white crystals of 2,5-dimethoxy-N-formyl-4-methylamphetamine. An analytical sample from ethyl formate gave granular white crystals.

  To a stirred suspension of 4.0 g LAH in 250 mL anhydrous Et2O at reflux and under an inert atmosphere, there was added, by the shunted Soxhlet technique, 4.2 g of 2,5-dimethoxy-N-formyl-4-methylamphetamine as rapidly as its solubility in hot Et2O would allow. The mixture was held at reflux for 24 h and then stirred at room temperature for several additional days. The excess hydride was destroyed with the addition of dilute H2SO4 (20 g in 500 mL water) followed by the additional dilute H2SO4 needed to effect a clear solution. The Et2O

  was separated, and the aqueous phase extracted with 100 mL Et2O and then with 2x250 mL CH2Cl2. Following the addition of 100 g potassium sodium tartrate, the mixture was made basic with 25% NaOH. The clear aqueous phase was extracted with 3x250 mL CH2Cl2 These extracts were pooled, and the solvent removed under vacuum. The residual amber oil was dissolved in 400 mL anhydrous Et2O, and saturated with hydrogen chloride gas. The white crystals that formed were removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 4.2 g of product with a mp of 131.5-133.5 !C. This product was recrys-tallized from 175 mL boiling ethyl acetate to give 3.5 g 2,5-dimethoxy-4,N-di-methylamphetamine hydrochloride (BEATRICE) as pale pink crystals with a mp of 136-137 !C. A sample obtained from a preparation that employed the methyl sulfate methylation of the benzaldehyde adduct of DOM had a mp of 125-126 !C and presented a different infra-red spectrum. It was, following recrystallization from ethyl acetate, identical to the higher melting form in all respects.

 

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