Pihkal

by Alexander Shulgin

  At the time that the FDA issued its proclamation of dangerous drugs (in the mid-1960Us), MMDA was being talked about, and in fact it had just become available commercially in England through the Koch Light Industries. But to my knowledge it had never appeared on the street, so its having being swept into the listings of evil drugs was simply a coincidence of bad timing. The close resemblance of initials between MMDA, and the currently notorious MDMA, has led to no small amount of confusion in the popular press. They remain totally separate and completely different drugs.

  133 MMDA-2; 2-METHOXY-4,5-METHYLENEDIOXYAMPHETAMINE

  SYNTHESIS: A solution of 11.5 g pellet KOH (85%) in 75 mL EtOH was treated with 25 g sesamol followed by 27 g methyl iodide. This was brought to reflux on the steam bath. Salt formation was apparent in 20 min, and refluxing was main-tained for a total of 4 h. The solvent was removed under vacuum, and residue poured into 400 mL H2O. This was acidified with HCl and extracted with 3x150 mL CH2Cl2. The pooled extracts were washed with 3x100 mL 5% NaOH, which removed most of the color. The solvent was removed under vacuum to provide 24.0 g of 3,4-methylenedioxyanisole as a pale amber oil.

  A mixture of 56.4 g POCl3 and 49.1 g N-methylformanilide was allowed to stand for 40 min and then it was poured into a beaker containing 64

  g 3,4-methylenedioxyanisole. There was an immediate exothermic reaction with darkening and the generation of bubbles. This was heated on the steam bath for 1 h, then poured into 1 L H2O with extremely vigorous stirring. The dark brown phase was quite opaque, and then there was a sudden lightening of color with the generation of a fine pale yellow solid. Stirring was continued for 2 h, then these crystals were removed by filtration. This crude product was recrystallized from 400 mL boiling MeOH yielding, after filtering, washing, and air drying to constant weight, 44.1 g 2-methoxy-4,5-methylenedioxybenzaldehyde with a mp of 110-111 !C.

  Only one positional isomer was visible in the final product by GC, but extraction of the original mother liquors with CH2Cl2 produced, after evaporation of the solvent under vacuum, 2 g of a red oil that showed two earlier peaks on OV-17. These were consistent with about 1% of each of the two alternate positional isomers that could result from the Vilsmeier formylation reaction.

  A solution of 43 g 2-methoxy-4,5-methylenedioxybenzaldehyde in 185 g nitroethane was treated with 9.3 g anhydrous ammonium acetate and heated on the steam bath for 4.5 h. The excess nitroethane was removed under vacuum to give a residue that spontaneously crystallized. These solids were washed out mechanically with the aid of 200 mL cold MeOH, and the brilliant orange crystals recovered by filtering and air drying to constant weight. There was obtained 35.7

  g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene with a mp of 166-167 !C. This was not improved by recrystallization from IPA.

  Evaporation of solvent from the methanolic washes gave yellow solids (4.6 g melting at 184-186 !C) which, on recrystallization from THF/hexane, melted at 188-190 !C. This showed a molecular weight of 416 by chemical ionization mass spectroscopy (isobutane at 0.5 torr) and is the C20H20N2O8 adduct of one molecule each of nitrostyrene, aldehyde, and ammonia that frequently appears as a very insoluble impurity in aldehyde-nitroethane condensations that are catalyzed by ammonium acetate.

  To a refluxing suspension of 36 g LAH in 1 L anhydrous THF under an inert atmosphere, there was added 44.3 g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene in hot THF. The solubility was very low, so that it was necessary to use a heat lamp on the dropping funnel to maintain a clear solution for addition. The addition required 2 h and the reflux was maintained for 36 h. The reaction mixture was then cooled in an ice bath and there was added, in sequence and commensurate with heat evolution, 36 mL H2O, 36 mL 15%

  NaOH, and finally 108 mL H2O. The granular solids were removed by filtration and washed with THF. The combined filtrate and washes were stripped of solvent under vacuum yielding 58.8 g of a pale amber oil.

  This was dissolved in 100 mL IPA, neutralized with con-centrated HCl (20 mL was needed) and diluted with 500 mL anhydrous Et2O. More IPA was required to keep an oil phase from appearing. After the crystalline product was completely formed, it was removed by filtration, washed with IPA/Et2O, and finally with Et2O. Air drying gave 31.1 g of 2-methoxy-4,5-methylenedioxyamphetamine hydrochloride (MMDA-2) with a mp of 186-187 !C.

  DOSAGE: 25 - 50 mg.

  DURATION: 8 - 12 h.

  QUALITATIVE COMMENTS: (with 25 mg) Had some not-too-pleasant jangly effects Q this is not the smoothest of drugs. Duration: onset at 1

  1/2 hours (dose after lunch), acute 3 to 4 hours, seconal at 11 hours to stop residual effects so I could sleep. Occasionally from 5 to 10

  hours acute abdominal distress, resembling gas pains but unable to defecate. Abdominal muscles tight and hard. This occurred for about 15 minutes every hour or so. Rather unpleasant.

  (with 30 mg) There was the first subtle note at 45 minutes, and the slow development makes the changes easy to assimilate, but difficult to quantitate. My awareness is truly enhanced. Nothing is distorted, so there can be no misrepresentation as a result. This would be a good material to introduce someone to the slow-on slow-off type of experience. It would be impossible for any person, at this level, on this drug, to have a bad experience. This is very much like a slow MDA, perhaps 80 milligrams of it, and fully as controllable. The N-methyl of this is a must.

  (with 40 mg) The chemical is primarily a visual enhancer with only an extremely modest amount of visual distortion. The retinal activity was of a minor and non-threatening nature. The chemical seemed to facilitate empathic communication and the emotions felt strong and clean. Conversation flowed easily, without inhibitions or defensiveness. Anorexia accompanied experience. There was no impotence. There was some restless movement which dissipated with exercise (walking and playing frisbee). Next day woke feeling energetic, no muscular stiffness, alert. I would repeat this experience.

  (with 50 mg) I was coming on within 40-60 minutes, easy and slow, but the body was +3 before the mind. The mental was strange for the first 2-3 hours Q I called it 'High Sierras' Q realistic, dispassionate, not kind. Some dark areas are persistent. Watched last half of Circus of Dr. Lao and the whole feeling changed from pornographic to erotic.

  Delightful. Some fantasy. On coming down, sleep was difficult. The body feels unexpectedly depleted. Rubber legs and handwriting jerky.

  EXTENSIONS AND COMMENTARY: A comparison of this material to MDA was often made by subjects who were familiar with both. But it is hard to separate that which is intellectualized from that which is felt. An awareness of the chemical structure immediately shows, of course, the close resemblance. There is the complete MDA molecule, with the addition of a methoxy group. And for the non-chemist, the name itself (MMDA-2) represents the second possible methoxy-MDA. Certainly one property that is shared with MDA is the broad variety of opinions as to the quality of its action. Some like it much, and some like it not at all. The N-methyl homologue was indeed made, for direct evaluation in comparison to N-methyl MDA (which is MDMA).

  The phenethylamine analog of MMDA-2 has been prepared by the condensation of the above benzaldehyde with nitromethane (in acetic acid with ammonium acetate catalyst, giving an equal weight of the nitrostyrene as deep orange crystals with a mp of 166-167 !C from ethyl acetate) followed by lithium aluminum hydride reduction (in ether). The product, 2-methoxy-4,5-methylenedioxyphenethylamine hydrochloride (2C-2) melted at 218-219 !C. There were no effects observed at up to 2.6 milligrams, but no higher trials were made. The 4-carbon homologue was made similarly (from the aldehyde and nitropropane but using tert-butylammonium acetate as a reagent in 100%

  excess and isopropanol as solvent, giving orange crystals melting at 98-99 !C from methanol) followed by reduction (with lithium aluminum hydride in ether) to give

  1-(2-methoxy-4,5-methylenedioxyphenyl)-2-aminobutane hydrochloride (4C-2) with a mp of 172-174 !C. This material has never even been tasted.

  The Tweetio homologue of MMDA-2 has been
tasted, however. This is 2-ethoxy-4,5-methylenedioxyamphetamine, or EMDA-2. The allyl ether of sesamol (3,4-methylenedioxy-allyloxybenzene) was rearranged to the 2-allyl phenol which was, in turn, converted to the ethyl ether.

  Reaction with tetranitromethane gave the nitrostyrene intermediate which had a mp of 120-121 !C. The final hydrochloride salt of EMDA-2

  had a mp of 188-188.5 !C. At 135 milligrams, there have been reported eyes-closed visual phenomena, with intense colors. The overall duration is similar to MMDA-2 (some 10 hours) and there are reported sleep disturbances. At 185 milligrams, the feelings were intensified, there were Rmarvelous eyes-closed visuals (the colors were incredible), good concentration, but distinct body-tingles and rushes.S The time span was about 12 hours from start to finish, but it proved to be impossible to sleep afterwards. This homologue is thus about a third the potency of MMDA-2.

  134 MMDA-3a; 2-METHOXY-3,4-METHYLENEDIOXYAMPHETAMINE

  SYNTHESIS: To a solution of 100 g of 2,3-dihydroxyanisole in 1 L dry acetone there was added 110 g of powdered anhydrous K2CO3 followed by 210 g of methylene iodide. This was brought up to a reflux on the steam bath. There was a sudden appearance of a solid phase, and then a gentle reflux was maintained for three days, during which time much of the heavy solid that initially formed had redissolved. The reaction mixture was filtered to remove the insoluble salts, and these were washed with hot acetone. The combined mother liquor and washes were stripped of solvent under vacuum, leaving a solid residue. This was leached with several portions of boiling hexane. These were pooled, and removal of the solvent under vacuum provided 53.6 g of 2,3-methylenedioxyanisole as white crystals with a sharp spicy smell.

  A mixture of 120 g N-methylformanilide and 137 g POCl3 was allowed to incubate at ambient temperature for 0.5 h, then there was added 53 g of crude 2,3-methylenedioxyanisole. The dark reaction mixture was heated on the steam bath for 2 h and then poured into a beaker filled with shaved ice. This was stirred until hydrolysis was complete, and the black, almost crystalline gunk that separated was removed by filtration. The 53.6 g of crude product was analyzed by GC using an ethylene glycol succinate column at 190 !C. Three peaks were apparent and had baseline separation. The major peak at 7.8 min constituted 82% of the product and was 2-methoxy-3,4-methylenedioxybenzaldehyde.

  A minor peak at 12.0 min represented 16% of the product and was the positional isomer 4-methoxy-2,3-methylenedioxybenzaldehyde. A trace component (2%) lay intermediate (at 9.5 min) and was myristicinaldehyde. The mps of the two major benzaldehydes were sufficiently different that they could serve as means of identification. The major product was obtained directly from the black gunk by repeated extraction with boiling cyclohexane which, upon removal of the solvent, gave 33.1 g of a yellow-colored product.

  This, upon one additional recrystallization from boiling cyclohexane, gave 24.4 g of 2-methoxy-3,4-methylenedioxybenzaldehyde as pale yellow crystals with a mp of 103-105 !C. The mother liquors were pooled and, after removal of all volatiles under vacuum, yielded an amber-colored solid that upon recrystallization provided a yellowish crystals.

  These, after yet another crystallization from cyclohexane, gave 4.1 g of 4-methoxy-2,3-methylenedioxybenzaldehyde with a mp of 85-86 !C.

  This latter isomer was used in the synthesis of MMDA-3b.

  To a solution of 3.5 g 2-methoxy-3,4-methylenedioxybenzaldehyde in 14

  g acetic acid there was added 1.4 g anhydrous ammonium acetate and 2.3

  mL of nitroethane. The mixture was brought to reflux and held there for 35 min. It was then quenched by the addition of 40 mL H2O, knocking out an orange, gummy solid. This was removed by filtration, and recrystallized from 50 mL boiling MeOH. After cooling for a few h in an ice bath, the bright yellow crystals were removed by filtration, washed with MeOH and air dried to constant weight, yielding 2.15 g 1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene. The mp was 106-107 !C. Recrystallization from EtOH raised this mp to 109.5-110.5

  !C.

  A suspension of 2.2 g LAH in 300 mL anhydrous Et2O under an inert atmosphere was brought to a gentle reflux. The reflux condensate was passed through a modified Soxhlet thimble containing 1.95 g 1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene effectively adding it, over the course of 0.5 h, to the reaction mixture as a saturated Et2O solution. The mixture was maintained at reflux for 16

  h. After cooling to 0 !C with an ice bath, the excess hydride was destroyed by the addition of 1.5 N H2SO4. The phases were separated, and the aqueous phase washed with 2x100 mL Et2O. To the aqueous phase there was added 50 g potassium sodium tartrate followed by sufficient 25% NaOH to raise the pH >9. This was then extracted with 3x100 mL

  CH2Cl2, and the solvent from the pooled extracts removed under vavuum.

  The residual white oil was dissolved in 250 mL anhydrous Et2O, and saturated with anhydrous HCl gas. There was produced a crop of white microcrystals of 2-methoxy-3,4-methylenedioxyamphetamine hydrochloride (MMDA-3a) which was removed by filtration, washed with Et2O, and air dried to a constant weight of 1.2 g. The mp was 154-155 !C.

  DOSAGE: 20 - 80 mg.

  DURATION: 10 - 16 h.

  QUALITATIVE COMMENTS: (with 20 mg) I became aware at about an hour, and an hour later I found myself suddenly caught up in the marvelous world of insects. Right alongside a pile of bricks I saw a measuring worm, and with great tenderness and patience I picked him up, observed his fore and aft 'feet' and finally replaced him and watched him acclimate himself. There was also a spider on the bricks, and I was compelled to watch him in action. I was grateful that I was not being observed. Time was moving slowly, and I felt I should intentionally move slowly, so as not to exhaust myself.

  (with 40 mg) This developed between one and two hours into it, and there were considerable body tremors. Talking directed the energy outwards, and I became aware of a visually sparkling world about me.

  I started dropping way too soon; it would have been interesting to have gone higher. By early evening I was left only with an awareness of some residual physical hypersensitivity, and there was light diarrhea. I am not at all sure just what to compare this drug to. It is gentle.

  (with 60 mg) There were visuals of a soft sort Q things moved with eyes open, and with eyes closed the music was great. There seemed to be some lasting stimulation, but it didnUt get in the way of sleeping.

  The next morning, however, I was still on. A good compound.

  EXTENSIONS AND COMMENTARY: The term MMDA-3a has the feel of being complicated, but there is a reason for the code. As had been mentioned, MMDA was the initials for methoxy (the M) methylenedioxy (the MD) amphetamine (the A). And with a molecule of amphetamine there are six ways of sticking these two groupings on the aromatic ring. The numbers 1-6 had already been assigned to the six ways of sticking three methoxyl groups onto an amphetamine molecule (with the trimethoxyamphetamines, the TMAUs) and I decided to hew to the same convention with the methylenedioxy counterparts. However, there are two #3's (the methoxy and the methylenedioxy can go onto the three oxygen atoms in a row in two different ways, whereas the three methoxys can go on in just one way) and there can be no #6 (since a methylenedioxy must, perforce, have two oxygens that are adjacent, and there are none to be so found in the 2,4,6-orientation of TMA-6). So, with two possible MMDA-3's it becomes reasonable, in fact essential, to name one of them RaS and the other RbS. The RaS orientation occurs in nature as the essential oil croweacin, or 1-allyl-2-methoxy-3,4-methylenedioxybenzene. It thus can allow MMDA-3a to be classified as an Essential Amphetamine, since it can arise, in principle, by amination in the liver in vivo. But in the laboratory, croweacin is certainly not a practical starting material in this synthesis.

  I have been told of a number of clinical trials that have explored MMDA-3a at considerably higher levels, but I have no explicit quotations to give, and the details are quite sketchy. Three trials at 80 milligrams, and one at 100 milligrams, all made comparisons, in both quantity and quality of the experience, to 100 micrograms of LSD.

>   However, two events occurred that may or may not be related to these trials; one subject had a spontaneous peak experience five days after the experiment, and another made a symbolic suicide attempt.

  And, as with MMDA-2, both the 2-carbon RphenethylamineS analogue and the 4-carbon RARIADNES analogue of MMDA-3a have been made. The phenethylamine analog was prepared by the condensation of 7.6 g of the above benzaldehyde with nitromethane (in acetic acid with ammonium acetate catalyst, giving 5.4 g of the nitrostyrene with a mp of 115.5-116.5 !C from methanol) followed by lithium aluminum hydride reduction (in ether). The product,

  2-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (2C-3a) melted at 143-145 !C. A series of subjective evaluations were made, and there are reports of marginal effects in the 40 to 120 milligram range. At 40 milligrams, perhaps the hint of a psychic energizer; at 65 milligrams, there was a pleasant mood elevation; at 80 milligrams, there was a brief paresthetic twinge noted at about the hour and a half point, and at 120 milligrams, about the same at one hour, and then nothing. The fact that there can be such a modest change of effect over a three-fold range of dosage suggests that this compound might have some merit as an anti-depressant. It would be interesting to know if it blocks serotonin reuptake!

  The 4-carbon analog was made similarly (from the aldehyde and nitropropane but using tert-butylammonium acetate as a reagent in 100%

  excess and isopropanol as solvent, giving bright yellow crystals melting at 105.5-106.5 !C from 25 volumes of boiling methanol) followed by reduction (with lithium aluminum hydride in ether) to give 1-(2-methoxy-3,4-methylenedioxyphenyl)-2-aminobutane hydrochloride (4C-3a) with a mp of 183-185 !C with prior sintering at 173 !C. This material has been tasted at up to 3.5 milligrams with nothing noted.