|[3D .mol structure]|
In 400 mL anhydrous Et2O there was dissolved 40.3 g N-cyclohexyl-3,4-methylenedioxybenzylidenimine and 30 mL N,N,N',N'-tetramethylethylenediamine (TMEDA). This solution was put under an inert atmosphere, and with good stirring brought to -78 °C with an external dry ice/acetone bath, which produced a light white crystalline precipitate. There was then added 120 mL of 1.55 M butyllithium, which produced an immediate darkening and a dissolving of the fine precipitate. After 10 min stirring, there was added 20 mL of dimethyl disulfide. The color immediately vanished and there was the formation of a white precipitate. The temperature was allowed to return to ice bath temperature, and then all volatiles were removed under vacuum. The residue was poured into 500 mL H2O and acidified with HCl. After heating for 1 h on the steam bath, the reaction mixture was cooled, producing a gummy solid that was shown to be a complex mixture by TLC. But there was a single fluorescent spot that was the product aldehyde and it was pursued. Extraction with 3x75 mL CH2Cl2 gave, after pooling and stripping of the solvent, a residue which was extracted with four separate passes, each with 75 mL boiling hexane. The deposited crystals from each were separated, and all recrystallized from boiling MeOH to give 3.3 g of 3,4-methylenedioxy-2-(methylthio)benzaldehyde, with a mp of 77-80 °C.
To a solution of 3.0 g 3,4-methylenedioxy-2-(methylthio)benzaldehyde in 25 mL IPA there was added 2 mL nitroethane, 0.11 mL ethylenediamine and 0.1 mL acetic acid. This was held at reflux temperature for 18 h, and the solvents removed under vacuum. The residue showed a total of eight spots on TLC analysis, extending from the origin to the spot of the product nitrostyrene itself. Trituration of this residue under 25 mL MeOH gave a crude nitrostyrene which was, after separation, recrystallized from 20 mL of boiling MeOH. The final isolation of 1-(3,4-methylenedioxy-2-methylthiophenyl)-2-nitropropene gave 0.5 g of a product that had a mp of 94-95 °C. The mixed mp with the nitrostyrene from piperonal (mp 97-98 °C) was soundly depressed (mp 67-79 °C).
A solution of AH was prepared by the treatment of a solution of 0.5 g LAH in 10 mL THF, at 0 °C and under He, with 0.32 mL 100% H2SO4. A solution of 0.45 g 1-(3,4-methylenedioxy-2-methylthiophenyl)-2-nitropropene in 10 mL THF was added dropwise, and the stirring was continued for 1 h. After a brief period at reflux, the reaction mixture was returned to room temperature, and the excess hydride destroyed by the addition of IPA. The salts were converted to a filterable mass by the addition of 5% NaOH, and after filtering and washing with IPA, the combined filtrate and washings were stripped of solvent under vacuum. The residue was dissolved in dilute H2SO4 which was washed with 3x75 mL CH2Cl2. After alkalinification with 25% aqueous NaOH, the product was extracted with 2x75 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum. Distillation of the residue gave a fraction that boiled at 137-150 °C at 0.3 mm/Hg and weighed 0.3 g. This was dissolved in 1.6 mL IPA, neutralized with 6 drops of concentrated HCl, warmed to effect complete solution, and diluted with 4 mL of anhydrous Et2O. The formed crystals were collected by filtration, and after Et2O washing and air drying to constant weight, gave 0.3 g 3,4-methylenedioxy-2-methylthioamphetamine hydrochloride (2T-MMDA-3a).
DOSAGE: greater than 12 mg.
EXTENSIONS AND COMMENTARY: And visions of sugar-plums danced through their heads. There are many trisubstituted amphetamine analogues that have been documented with varying degrees of activity. There are six TMA's and if one were to systematically make every possible thio-analogue of each of these, there would be a total of sixteen thio-analogues of the TMA. Let's go for it, said I to myself. Let's get the 16 thio analogues in hand. That is where the action's at. But hold on a minute. Each and every MMDA isomer has, by definition, three possible thio analogues, so there are eighteen more possible thio compounds just with them. Sure, let's make them all! It will be an unprecedented coup for students of structure-activity relationships. Let's whip out some 34 compounds, and test them all, and maybe we will begin to understand just why those which are active are, indeed, active. And maybe not.
Anyway, this was the most manic of all manic programs ever, involving thio-analogues. And it was totally compelling. Another synthetic clue stemmed from the fact that vanillin also formed the cyclic carbonate with sodium thiocyanate and it could, in principle, be brought around in time to 3-methoxy-5,4-methylenethiooxyamphetamine, or 5T-MMDA. That made two of the magic analogues, and only some 32 to go. What a marvelous task for a graduate student. (What a horribly dull task for a graduate student.) But in any case there was no graduate student, and this appeared to be the end of the line. Some day, let's make all these possibilities. A magnificent tour-de-force, but at the present time, not worth the effort. Other directions are more exciting and more appealing.
A last note of simple humor. One of the compounds used in this preparation was N,N,N',N'-tetramethylethylenediamine, which has been abbreviated TMEDA. There is a pattern, within any active inner clique of research chemists intently pursuing a goal, to begin condensing complex comcepts into deceptively simple terms. We "MOM-ed the hydroxy group of the T-BOC-ed amine." I have recently heard the above tetramethyl monster referred to in the chemist's jargon as a pronounced, rather than a spelled out, word. It sounds very much like "tomato" spoken by a native of the Bronx.
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