Pihkal

by Alexander Shulgin

  SYNTHESIS: To a solution of 50 g 3,4-dihydroxy-5-methoxybenzaldehyde in 100 mL distilled acetone there was added 70 g ethylene bromide and 58 g finely powdered anhydrous K2CO3. The mixture was held at reflux for 5 days. This was then poured into 1.5 L H2O and extracted with 4x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a residue which was distilled at 19 mm/Hg. Several of the fractions taken in the 203-210 !C range spontaneously crystallized, and they were pooled to give 18.3 g of 3-methoxy-4,5-ethylenedioxybenzaldehyde as white solids with a mp of 80-81 !C. A small sample with an equal weight of malononitrile in EtOH treated with a few drops of triethylamine gave 3-methoxy-4,5-ethylenedioxybenzalmalononitrile as pale yellow crystals from EtOH with a mp of 153-154 !C.

  A solution of 1.50 g 3-methoxy-4,5-ethylenedioxybenzaldehyde in 6 mL

  acetic acid was treated with 1 mL nitroethane and 0.50 g anhydrous ammonium acetate, and held on the steam bath for 1.5 h. To the cooled mixture H2O was cautiously added until the first permanent turbidity was observed, and once crystal-lization had set in, more H2O was added at a rate that would allow the generation of additional crystals.

  When there was a residual turbidity from additional H2O, the addition was stopped, and the beaker held at ice temperature for several h.

  The product was removed by filtration and washed with a little 50%

  acetic acid, providing 0.93 g

  1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene as dull yellow crystals with a mp of 116-119 !C. Recrystallization of an analytical sample from MeOH gave a mp of 119-121 !C.

  A stirred suspension of 6.8 g LAH in 500 mL anhydrous Et2O under an inert atmosphere was brought up to a gentle reflux. A total of 9.4 g 1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene in warm Et2O was added over the course of 0.5 h. Refluxing was maintained for 6 h, and then the reaction mixture was cooled and the excess hydride destroyed by the cautious addition of 400 mL 1.5 N H2SO4. The two clear phases were separated, and the aqueous phase was brought to pH of 6 by the addition of a saturated Na2CO3 solution. This was filtered free of a small amount of insolubles, and the clear filtrate was heated to 80

  !C. To this there was added a solution of 9.2 g picric acid (90%

  material) in 100 mL boiling EtOH, and the clear mixture allowed to cool in an ice bath. Scratching generated yellow crystals of the picrate salt. This salt was filtered free of the aqueous environment, treated with 50 mL of 5% NaOH, and stirred until the picric acid was totally in the form of the soluble sodium salt. This was then extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue weighed 6.0 g, and was dissolved in 100 mL anhydrous Et2O, and saturated with dry HCl gas. The white solids that formed were filtered free of the Et2O, and ground up under 50 mL of slightly moist acetone, providing 4.92 g of 3-methoxy-4,5-ethylenedioxyamphetamine hydrochloride monohydrate (MEDA) as white crystals.

  DOSAGE: greater than 200 mg.

  DURATION: unknown.

  EXTENSIONS AND COMMENTARY: There are times when the Gods smile in unexpectedly nice ways. Having found the activity of MMDA, the RscientificS thing to do would be to compare it against the other RpsychotomimeticS amphetamine that was known at that time (this was 1962), namely TMA. Comparing their structures, the only difference of any kind was that two of the adjacent methoxyl groups of TMA were replaced with a 5-membered ring, called the methylenedioxy ring.

  Where does one go next? Some perverse inspiration suggested increasing the size of this ring to a 6-membered ring, the ethylenedioxy (or dioxene) homologue. Well, if you thought that getting myristicinaldehyde was a difficulty, it was nothing compared to getting this 6-membered counterpart. But I huffed and I puffed, and I did make enough to taste and to evaluate. And it was here that I got the divine message! No activity!! So, rather than being condemned forever a la Sisyphus to push ever larger rings up my psyche, I gave myself permission to pursue another path. The message was: RDonUt change the groups. Leave them as they are, but relocate them instead.S And that led directly to TMA-2 and its story.

  A couple of diversions may be mentioned here. Before the blessed inactivity of MEDA was established, the 7-membered ring counterpart, 3-methoxy-4,5-trimethylenedioxyamphetamine (MTMA) was prepared by essentially the same procedure. The above 3-methoxy-4,5-dihydroxybenzaldehyde with trimethylene bromide gave 3-methoxy-4,5-trimethylenedioxybenzaldehyde, white solids, with a malononitrile derivative with a mp of 134-135 !C; the aldehyde with nitroethane gave the nitropropene with a mp of 86-87 !C; and this with LAH gave MTDA as the hydrochloride (mp 160-161 !C) again isolated first as the picrate. It had been tasted at up to an 8 milligram dosage (no activity, but none expected) before being abandoned. And, an initial effort was made to synthesize a five-member ring (methylenedioxy) with a methyl sticking out from it. This ethylidine homologue got as far as the aldehyde stage. The reaction between 3,4-dihydroxy-5-methoxybenzaldehyde and 1,1-dibromoethane in acetone containing anhydrous potassium carbonate gave a minuscule amount of a product that was a two-component mixture. This was resolved by dozens of separate injections into a preparatory gas chromatography system, allowing the isolation of the second of the two components in a quantity sufficient to demonstrate (by NMR spectroscopy) that it was the desired 3-methoxy-4,5-ethylidinedioxybenzaldehyde. Starting with the pre-prepared dipotassium salt or the lead salt of the catecholaldehyde gave nothing. With no activity being found with MEDA, all was abandoned.

  There are some comments made under MDA for successful chemistry (using a different approach) alo#ng these lines when there is no methoxyl group present. These are the compounds EDA and IDA. But the pharmacology was still not that exciting.

  121 MEE; 4,5-DIETHOXY-2-METHOXYAMPHETAMINE

  SYNTHESIS: To a solution of 166 g bourbonal in 1 L MeOH there was added a solution of 66 g KOH pellets in 300 mL H2O. There was then added 120 g ethyl bromide, and the mixture was held at reflux on the steam bath for 3 h. The reaction was quenched with three volumes of H2O, and made strongly basic by the addition of 25% NaOH. This was extracted with 3x300 mL CH2Cl2, and the pooled extracts stripped of solvent under vacuum. There remained 155 g of 3,4-diethoxybenzaldehyde as a fluid oil that had an infra-red spectrum identical (except for being slightly wet) to that of a commercial sample from the Eastman Kodak Company.

  A solution of 194 g 3,4-diethoxybenzaldehyde in 600 g glacial acetic acid was arranged in a flask that could be magnetically stirred, yet cooled as needed with an external ice bath. A total of 210 g of 40%

  peracetic acid in acetic acid was added at a rate such that, with ice cooling, the exothermic reaction never raised the internal temperature above 26 !C. The reaction developed a deep red color during the 2 h needed for the addition. At the end of the reaction the mixture was quenched by the addition of three volumes of H2O, and the remaining acidity was neutralized by the addition of solid Na2CO3 (700 g was required). This aqueous phase was extracted several times with CH2Cl2, and the solvent was removed from the pooled extracts under vacuum. The residue was a mixture of the intermediate formate ester and the end product phenol. This was suspended in 800 mL 10% NaOH, and held on the steam bath for 1.5 h. After cooling, this was washed once with CH2Cl2 (discarded) and then acidified with HCl. There was the formation of an intensely hydrated complex of the product phenol, reminiscent of the problem encountered with 3-ethoxy-4-methoxyphenol.

  This was worked up in three parts. The entire acidified aqueous phase was extracted with Et2O (3x200 mL) which on evaporation gave 80 g of an oil. The hydrated glob was separately ground up under boiling CH2Cl2 which, on evaporation, gave an additional 30 g of oil, and the aqueous mother liquor from the glob was extracted with 2x200 mL CH2Cl2

  which provided, after removal of the solvent, an additional 10 g.

  These crude phenol fractions were combined and distilled at 1.5 mm/Hg.

  Following a sizeable forerun, a fraction boiling at 158-160 !C was the anhydrous product, 3,4-diethoxyphenol. It was a clear, amber oil, and weighed 70.0 g. The slig
htest exposure to H2O, even moist air, give a solid hydrate, with mp of 63-64 !C. This phenol can be used for the synthesis of MEE (this recipe) or for the preparation of EEE (see the separate recipe). A solution of 2.0 g of this phenol in 5 mL CH2Cl2

  was diluted with 15 mL hexane. This was treated with 2 g methyl isocyanate followed by a few drops of triethylamine. After about 5

  min, white crystals formed of 3,4-diethoxyphenyl-N-methyl carbamate, with a mp of 90-91 !C.

  A solution of 26.6 g 3,4-diethoxyphenol in 50 mL MeOH was mixed with another containing 9.6 g KOH pellets dissolved in 200 mL hot MeOH.

  There was then added 21.4 g methyl iodide, and the mixture was held at reflux for 2 h on the steam bath. This was then quenched in 3 volumes of water, made strongly basic with 25% NaOH, and extracted with 3x150

  mL CH2Cl2. Evaporation of the solvent from the pooled extracts gave 19.3 g of 1,2-diethoxy-4-methoxybenzene (3,4-diethoxyanisole) as a clear, pale amber oil that solidified when cooled. The mp was 20-21

  !C.

  A mixture of 32.0 g N-methyl formanilide and 36.2 g POCl3 was allowed to stand until it was a deep red color (about 0.5 h). To this there was added 18.3 g 1,2-diethoxy-4-methoxybenzene and the exothermic reaction was heated on the steam bath for 2.5 h. This was then poured over 600 mL chipped ice, and the dark oily material slowly began lightening in color and texture. A light oil was formed which, on continued stirring, became crystalline. After the conversion was complete, the solids were removed by filtration producing, after removal of as much H2O as possible by suction, 26.9 g of crude aldehyde. A small sample pressed on a porous plate had a mp of 87.5-88.5 !C. Recrystallization of the entire damp crop from 50 mL

  boiling MeOH gave, after cooling, filtering, and air drying, 17.7 g of 4,5-diethoxy-2-methoxybenzaldehyde as fluffy, off-white crystals with a mp of 88-88.5 !C. A solution of 1.0 g of this aldehyde and 0.5 g of malononitrile dissolved in warm absolute EtOH was treated with 3 drops triethylamine. There was the immediate formation of crystals which were filtered and air dried to constant weight. The product, 4,5-diethoxy-2-methoxybenzalmalononitrile, was a bright yellow crystalline material, which weighed 1.0 g and had a mp of 156-157 !C.

  To a solution of 14.7 g 4,5-diethoxy-2-methoxybenzaldehyde in 46 g glacial acetic acid, there was added 8.0 g nitroethane and 5.0 g anhydrous ammonium acetate. The mixture was heated on the steam bath for 2 h, becoming progressively deeper red in color. The addition of a small amount of H2O to the hot, clear solution produced a slight turbidity, and all was allowed to stand overnight at room temperature.

  There was deposited a crop of orange crystals that was removed by filtration and air dried. There was obtained 7.0 g 1-(4,5-diethoxy-2-methoxyphenyl)-2-nitropropene as brilliant orange crystals that had a mp of 89-90.5 !C. This was tightened up, but not improved, by trial recrystallization from acetic acid, mp 89-90 !C, and from hexane, mp 90-90.5 !C. Anal. (C14H19NO5) C,H.

  To a gently refluxing suspension of 5.0 g LAH in 400 mL anhydrous Et2O

  under a He atmosphere, there was added 6.5 g 1-(4,5-diethoxy-2-methoxyphenyl)-2-nitropropene by allowing the condensing Et2O to drip into a shunted Soxhlet thimble containing the nitrostyrene. This effectively added a warm saturated solution of the nitrostyrene dropwise. Refluxing was maintained for 5 h, and the reaction mixture was cooled with an external ice bath. The excess hydride was destroyed by the cautious addition of 400 mL of 1.5 N

  H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 100 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was >9, and this was extracted with 3x200 mL CH2Cl2. Removal of the solvent under vacuum produced an off-white oil that was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas. The crystals of 4,5-diethoxy-2-methoxyamphetamine hydrochloride (MEE) that formed were very fine and slow to filter, but finally were isolated as a white powder weighing 5.4 g and melting at 178.5-180 !C. Anal.

  (C14H24ClNO3) C,H,N.

  DOSAGE: greater than 4.6 mg.

  DURATION: unknown.

  EXTENSIONS AND COMMENTARY: There were early trials made with MEE, before it became known what direction the ethoxy substitution results would take. A number of progressive trials, up to a dosage of 4.6

  milligrams, were without any central effects at all.

  There is an instinct in structure-activity studies to think of a change as a success or a failure, depending on whether there is an increase or a decrease in the desired activity. But if one were to look at the effects of putting an ethoxy group onto TMA-2 in place of a methoxy group as a way of decreasing the effectiveness, then the 4-position becomes the worst position (MEM is equipotent to TMA-2), and the 5-position is perhaps a little less bad (MME is almost as potent) and the 2-position is the best by far (EMM is out of it, potency-wise). In other words, in the comparison of the 2- and the 5-positions, the lengthening of the 5-position gives modest loss of activity, and the lengthening of the whatever in the 2-position is the most disruptive. With this as a basis for prediction, then MEE (which differs from MEM only by a lengthening of the 5-position substituent) might be only a little less active than MEM and, as MEM is about the same as TMA-2, it is distinctly possible that MEE may show activity in the area at dosages that are not much above the 25 to 50 milligram area. Of all the diethoxy homologues, it would be the most promising one to explore.

  Which brings to mind a quotation of a hero of mine, Mark Twain. RI like science because it gives one such a wholesome return of conjecture from such a trifling investment of fact.

  122 MEM; 2,5-DIMETHOXY-4-ETHOXYAMPHETAMINE

  SYNTHESIS: A solution of 83 g bourbonal (also called ethyl vanillin, or vanillal, or simply 3-ethoxy-4-hydroxybenzaldehyde) in 500 mL MeOH

  was treated with a solution of 31.5 g KOH pellets (85% material) dissolved in 250 mL H2O. There was then added 71 g methyl iodide, and the mixture was held under reflux conditions for 3 h. All was added to 3 volumes of H2O, and this was made basic with the addition of 25%

  NaOH. The aqueous phase was extracted with 5x200 mL CH2Cl2. The pooling of these extracts and removal of the solvent under vacuum gave a residue of 85.5 g of the product 3-ethoxy-4-methoxybenzaldehyde, with a mp of 52-53 !C. When this product was recrystallized from hexane, its mp was 49-50 !C. When the reaction was run with the same reactants in a reasonably anhydrous environment, with methanolic KOH, the major product was the acetal, 3-ethoxy-a,a,4-trimethoxytoluene.

  This was a white glistening product which crystallized readily from hexane, and had a mp of 44-45 !C. Acid hydrolysis converted it to the correct aldehyde above. The addition of sufficient H2O in the methylation completely circumvents this by-product. A solution of 1.0

  g of this aldehyde and 0.7 g malononitrile in 20 mL warm absolute EtOH, when treated with a few drops of triethylamine, gave immediate yellow color followed, in a few min by the formation of crystals.

  Filtration, and washing with EtOH, gave bright yellow crystals of 3-ethoxy-4-methoxybenzalmalononitrile with a mp of 141-142 !C.

  A well stirred solution of 125.4 g 3-ethoxy-4-methoxybenzaldehyde in 445 mL acetic acid was treated with 158 g 40% peracetic acid (in acetic acid) at a rate at which, with ice cooling, the internal temperature did not exceed 27 !C. The addition required about 45 min.

  The reaction mixture was then quenched in some 3 L H2O. There was the generation of some crystals which were removed by filtration. The mother liquor was saved. The solid material weighed, while still wet, 70 g and was crude formate ester. A small quantity was recrystallized from cyclohexane twice, to provide a reference sample of 3-ethoxy-4-methoxyphenyl formate with a mp of 63-64 !C. The bulk of this crude formate ester was dissolved in 200 mL concentrated HCl which gave a deep purple solution. This was quenched with water which precipitated a fluffy tan solid, which was hydrated phenolic product that weighed about 35 g, and melted in the 80-90 !C. range. The mother liquors of the above filtration were neutralized with Na2CO3, then extracted with 3x100 ml Et2O
. Removal of the solvent gave a residue of about 80 g that was impure formate (containing some unoxidized aldehyde). To this there was added 500 mL 10% NaOH, and the dark mixture heated on the steam bath for several h. After cooling, the strongly basic solution was washed with CH2Cl2, and then treated with 200 mL Et2O, which knocked out a heavy semi-solid mass that was substantially insoluble in either phase. This was, again, the crude hydrated phenol. The Et2O phase, on evaporation, gave a third crop of solids. These could actually be recrystallized from MeOH/H2O, but the mp always remained broad. When subjected to distillation conditions, the H2O was finally driven out of the hydrate, and the product 3-ethoxy-4-methoxyphenol distilled as a clear oil at 180-190 !C at 0.8 mm/Hg. This product, 45.1 g, gave a fine NMR

  spectrum, and in dilute CCl4 showed a single OH band at 3620 cm-1, supporting the freedom of the OH group on the aromatic ring from adjacent oxygen. Efforts to obtain an NMR spectrum in D2O immediately formed an insoluble hydrate. This phenol can serve as the starting material for either MEM (see below) or EEM (see separate recipe).

  To a solution of 12.3 g 3-ethoxy-4-methoxyphenol in 20 mL MeOH, there was added a solution of 4.8 g flaked KOH in 100 mL heated MeOH. To this clear solution there was then added 10.7 g methyl iodide, and the mixture held at reflux on the steam bath for 2 h. This was then quenched in 3 volumes H2O, made strongly basic with 10% NaOH, and extracted with 3x100 mL CH2Cl2. Removal of the solvent from the pooled extracts under vacuum gave 9.4 g of an amber oil which spontaneously crystallized. The mp of 1,4-dimethoxy-2-ethoxybenzene was 42-43.5 !C, and was used, with no further purification, in the following step.

  A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed to stand for 0.5 h, producing a deep claret color. To this there was added 9.2 g 1,4-dimethoxy-2-ethoxybenzene, and the mixture was held on the steam bath for 2 h. It was then poured into chipped ice and, with mechanical stirring, the dark oily phase slowly became increasingly crystalline. This was finally removed by filtration, providing a brown solid mat which showed a mp of 103.5-106.5 !C. All was dissolved in 75 mL boiling MeOH which, on cooling, deposited fine crystals of 2,5-dimethoxy-4-ethoxybenzaldehyde that were colored a light tan and which, after air drying to constant weight, weighed 8.5