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#98 MADAM-6


SYNTHESIS: A mixture of 102 g POCl3 and 115 g N-methylformanilide was allowed to stand for 0.5 h at room temperature during which time it turned a deep claret color. To this there was added 45 g 3,4-methylenedioxytoluene and the mixture was held on the steam bath for 3 h. It was then added to 3 L H2O. Stirring was continued until the oil which had separated had become quite firm. This was removed by filtration to give a greenish, somewhat gummy, crystalline solid, which was finely ground under 40 mL MeOH and again filtered giving, when air dried, 25 g of an almost white solid. Recrystallization of a small sample from methylcyclopentane gave ivory-colored glistening crystals of 2-methyl-4,5-methylenedioxybenzaldehyde with a mp of 88.5-89.5 °C. In the infra-red, the carbonyl was identical to that of the starting piperonal (1690 cm-1) but the fingerprint was different and unique, with bands at 868, 929, 1040 and 1052 cm-1.

A solution of 23 g 2-methyl-4,5-methylenedioxybenzaldehyde in 150 mL nitroethane was treated with 2.0 g anhydrous ammonium acetate and heated on the steam bath for 9 h. The excess solvent was removed under vacuum to give a dark yellow oil which was dissolved in 40 mL hot MeOH and allowed to crystallize. The solids were removed by filtration, washed modestly with MeOH and air dried, to give 21.2 g of 1-(2-methyl-4,5-methylenedioxyphenyl)-2-nitropropene as beautiful yellow crystals with a mp of 116-118 °C. Recrystallization of an analytical sample from MeOH gave lustrous bright yellow crystals with a mp of 120-121 °C. Anal. (C11H11NO4) C,H,N.

A suspension of 54 g electrolytic elemental iron in 240 g glacial acetic acid was warmed on the steam bath, with frequent stirring. When the reaction between them started, there was added, a portion at a time, a solution of 18.2 g 1-(2-methyl-4,5-methylenedioxyphenyl)-2-nitropropene in 125 mL warm acetic acid. The orange color of the nitrostyrene solution became quite reddish, white solids of iron acetate appeared, and a dark tomato-colored crust formed which was continuously broken back into the reaction mixture. Heating was continued for 1.5 h, and then all was poured into 2 L H2O. All the insolubles were removed by filtration, and these were washed well with CH2Cl2. The filtrate and washes were combined, the phases separated, and the aqueous phase extracted with 2x100 mL additional CH2Cl2. The combined organics were washed with 5% NaOH, and the solvent removed under vacuum. The residue weighed 15.9 g, and was distilled at 90-110 °C at 0.4 mm/Hg to give 13.9 g of 2-methyl-4,5-methylenedioxyphenylacetone that spontaneously crystallized. A small sample from methylcyclopentane had a mp of 52-53 °C, another from hexane a mp of 53-54 °C, and another from MeOH a mp of 54-55 °C. Anal. (C11H12O3) H; C calcd, 68.73; found 67.87, 67.84.

To a stirred solution of 30 g methylamine hydrochloride in 200 mL warm MeOH there was added 13.5 g 2-methyl-4,5-methylenedioxyphenylacetone followed, after returning to room temperature, by 7 g sodium cyanoborohydride. There was added HCl as needed to maintain the pH at approximately orange on external damp universal pH paper. After a few days, the reaction ceased generating base, and all was poured into 2 L dilute H2SO4 (caution, HCN evolved). This was washed with 3x75 mL CH2Cl2, made basic with 25% NaOH, and the resulting mixture extracted with 3x100 CH2Cl2. The pooled extracts were stripped of solvent under vacuum and the residue, 15 g of a pale amber oil, was distilled at 95-110 °C at 0.4 mm/Hg. There was obtained 12.3 g of a white oil that was dissolved in 60 mL IPA, neutralized with approximately 5.5 mL concentrated HCl, and crystals of the salt formed spontaneously. These were loosened with the addition of another 10 mL IPA, and then all was diluted by the addition of an equal volume of anhydrous Et2O. The white crystals were separated by filtration, Et2O washed, and air dried to give 14.1 g of 2,N-dimethyl-4,5-methylenedioxyamphetamine hydrochloride (MADAM-6) as a brilliant white powder with a mp of 206-207 °C. Anal. (C12H18ClNO2) C,H.

DOSAGE: greater than 280 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 180 mg) There is a hint of good things there, but nothing more than a hint. At four hours, there is no longer even a hint.

(with 280 mg) I took 150 milligrams, waited an hour for results, which was niente, nada, nothing. Took supplements of 65 milligrams twice, an hour apart. No effect. Yes, we giveth up.

EXTENSIONS AND COMMENTARY: The structure of MADAM-6 was designed to be that of MDMA, with a methyl group attached at what should be a reasonably indifferent position. In fact, that is the genesis of the name. MDMA has been called ADAM, and with a methyl group in the 6-position, MADAM-6 is quite understandable. And the other ortho-position is, using this nomenclature, the 2-position, and with a methyl group there, one would have MADAM-2. I should make a small apology for the choice of numbers. MDMA is a 3,4-methylenedioxy compound, and the least ambiguous numbering scheme would be to lock the methylenedioxy group inescapably at the 3,4-place, letting the other ring position numbers fall where they may. The rules of chemistry ask that if something is really a 3,4,6-orientation it should be renumbered as a 2,4,5-orientation. Let's quietly ignore that request here.

How fascinating it is, that a small methyl group, something that is little more than one more minor bump on the surface of a molecule that is lumpy and bumpy anyway, can so effectively change the action of a compound. A big activity change from a small structure change usually implies that the bump is at a vital point, such as a target of metabolism or a point of critical fit in some receptor site. And since 6-MADAM can be looked upon as 6-bump-MDMA, and since it is at least 3x less potent than MDMA, the implication is that the action of MDMA requires some unbumpiness at this position for its particular action. There are suggestions that the body may want to put a hydroxyl group right there (a 6-hydroxy-dopamine act), and it couldn't if there was a methyl group right there. The isopropylamine side chain may want a certain degree of swing-around freedom, and this would be restricted by a methyl bump right next to it. And there are all kinds of other speculations possible as to why that position should be open.

Anyway, MADAM-6 is not active. And the equally intriguing positional isomer, the easily made MADAM-2, will certainly contribute to these speculations. A quiz for the reader! Will 2,N-dimethyl-3,4-methylenedioxyamphetamine (MADAM-2) be: (1) Of much reduced activity, akin to MADAM-6, or (2) Of potency and action similar to that of MDMA, or (3) Something unexpected and unanticipated? I know only one way of finding out. Make the Schiffs' base between piperonal and cyclohexylamine, treat this with butyl lithium in hexane with some TMEDA present, add some N-methylformanilide, convert the formed benzaldehyde to a nitrostyrene with nitroethane, reduce this with elemental iron to the phenylacetone, reduce this in the presence of methylamine with sodium cyanoborohydride, then taste the result.

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